No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The effect of induced hyperthermia on the immune system
Abstract
Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.
... Elevated systemic levels of tumour necrosis factor a (TNF-a), interleukin 6 (IL-6) and interleukin 10 (IL-10) have been reported in AS patients compared to healthy controls, while soluble interleukin 2 receptor (sIL-2R) levels were decreased [5]. Previous in vitro and in vivo studies with core temperatures up to 42 C showed an increase of circulating interleukin 1 b (IL-1b), IL-6, interleukin 8 (IL-8) and TNF-a [6][7][8][9][10][11], whereas moderate hyperthermia treatment around 39 C enhanced anti-inflammatory T cell functions [8,[12][13][14][15][16][17][18]. Prolonged T cell activation up to 48 h after whole body hyperthermia has been demonstrated, accompanied by a marked shift of T cells into lymphoid tissues [12]. ...
... Previous in vitro and in vivo studies with core temperatures up to 42 C showed an increase of circulating interleukin 1 b (IL-1b), IL-6, interleukin 8 (IL-8) and TNF-a [6][7][8][9][10][11], whereas moderate hyperthermia treatment around 39 C enhanced anti-inflammatory T cell functions [8,[12][13][14][15][16][17][18]. Prolonged T cell activation up to 48 h after whole body hyperthermia has been demonstrated, accompanied by a marked shift of T cells into lymphoid tissues [12]. Numbers of natural killer (NK) cells and CD8+ T lymphocytes increased during whole body hyperthermia, while numbers of CD4+ T lymphocytes decreased [13,15]. ...
... the existing literature, describing an increase of circulating neutrophils following hyperthermia treatment due to stress induced mobilisation from the vessel walls [26]. Moreover, tissue trafficking and homing to lymph nodes, but also apoptosis, may account for the decrease in T lymphocytes and NK-cells [12,27]. Monocytes have previously been shown to be activated by hyperthermia, exhibiting reduced extravasation in order to be able to respond to pathogens in the bloodstream [28]. ...
Purpose: Exposure to increased environmental temperatures is commonly used as a non-pharmacological treatment modality in ankylosing spondylitis (AS). We aimed to investigate systemic immunological effects of moderate whole body hyperthermia in patients with AS compared to healthy control subjects. Materials and methods: Ten healthy control subjects and six AS patients underwent whole body hyperthermia treatment with 38.7-39 degrees C body core temperature over 60 min. Numbers of polymorphonuclear leucocytes and lymphocyte subsets, plasma concentrations of several acute phase reactants and cytokines, and gene expression levels of toll-like receptor 4 (TLR-4), interleukin 10 (IL-10) and heat shock protein beta 1 (HSPB1) were determined during and up to 24 h after treatment. Results: TLR-4, IL-10 and HSPB1 gene expression increased significantly up to 3 h post treatment, with an earlier, higher and more pronounced increase of IL-10 in patients with AS. An increase of natural killer cells and CD8+ T lymphocytes was noted during active heating, with a subsequent decrease up to 2 h after treatment. CD4+ T lymphocytes showed a short increase during active treatment in AS patients, while decreasing immediately after start of treatment in control subjects. Neutrophil granulocytes increased significantly up to 3 h after treatment, monocytes and B lymphocytes remained unchanged. Likewise, no significant changes were found concerning systemic cytokine concentrations and acute phase reactants. Conclusions: Our data support the concept of systemic immunological effects of moderate whole body hyperthermia in patients with AS.
... Other studies claimed that hyperthermia in this range is beneficial and enhances the immune response. [13][14][15] Our results demonstrate that LF-ThMS locally applied to the dorsal thorax of COVID-19 patients is safe, allowing increased SpO 2 levels during a single LF-ThMS intervention of 30 minutes. This is in line with models predicting the electrical [16] or thermal inactivation of SARS-CoV-2 [17] in the environment, or with the hypothesis that hydro-thermotherapy or photobiomodulation could help in the treatment of COVID-19 patients. ...
... The spike protein mediates cell entry via binding with angiotensin-converting enzyme 2 in host cells, and the nonstructural protein 1 is crucial for virus-host interaction. [28,29] Furthermore, there is evidence that an increase in tissue temperature can affect proteins and enhance the immune response [14,15] ; hence, it is tempting to speculate that hyperthermia produced by the LF-ThMS may acutely interfere with these viral proteins and improve respiratory function. ...
Severe acute respiratory syndrome coronavirus-2 may cause low oxygen saturation (SpO2) and respiratory failure in patients with coronavirus disease (COVID-19). Hence, increased SpO2 levels in COVID-19 patients could be crucial for their quality of life and recovery. This study aimed to demonstrate that a 30-minute single session of dorsal low-field thoracic magnetic stimulation (LF-ThMS) can be employed to increase SpO2 levels in COVID-19 patients significantly. Furthermore, we hypothesized that the variables associated with LF-ThMS, such as frequency, magnetic flux density, and temperature in the dorsal thorax, might be correlated to SpO2 levels in these patients.
Here we employed an LF-ThMS device to noninvasively deliver a pulsed magnetic field from 100 to 118 Hz and 10.5 to 13.1 milliTesla (i.e., 105 to 131 Gauss) to the dorsal thorax. These values are within the intensity range of several pulsed electromagnetic field devices employed in physical therapy worldwide. We designed a single-blind, sham-controlled, crossover study on 5 COVID-19 patients who underwent 2 sessions of the study (real and sham LF-ThMS) and 12 patients who underwent only the real LF-ThMS.
We found a statistically significant positive correlation between magnetic flux density, frequency, or temperature, associated with the real LF-ThMS and SpO2 levels in all COVID-19 patients. However, the 5 patients in the sham-controlled study did not exhibit a significant change in their SpO2 levels during sham stimulation. The employed frequencies and magnetic flux densities were safe for the patients. We did not observe adverse events after the LF-ThMS intervention.
This study is a proof-of-concept that a single session of LF-ThMS applied for 30 minutes to the dorsal thorax of 17 COVID-19 patients significantly increased their SpO2 levels. However, future research will be needed to understand the physiological mechanisms behind this finding.
The study was registered at ClinicalTrials.gov (Identifier: NCT04895267, registered on May 20, 2021) retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT04895267.
... The nuclear matrix shows damage at lower temperatures than other parts of the cell, with significant endothermic changes observed at 40°C [12]. Direct cell death in humans occurs at temperatures of around 41°C, with the rate of cell death increasing markedly with further temperature increases, primarily due to protein denaturation [13,14]. The microvasculature is affected rapidly during hyperthermia, with capillary dilation, vascular stasis and extravasation into the interstitium at a temperature of 40.5°C [15]. ...
... Gastrointestinal permeability and a pro-inflammatory response appear to occur as a consequence of increased thermal load, irrespective of the cause [14,[24][25][26][27]39]; whether corticosteroids are efficacious in hyperthermia of any aetiology is unclear but would also warrant further investigation. Identifying a particular cause of a raised temperature is often difficult, but may be non-infectious in up to two-thirds of cases [68], suggesting that steroid administration might prove to be beneficial even when the cause cannot be identified. ...
Severe hyperthermia from classical or exertional heatstroke, or from drug ingestion or other
non-infective pyrogens, is associated with a high mortality and morbidity. A systemic proinflammatory response occurs during heatstroke, characterised by elevated cytokines with
endotoxaemia from elevated lipopolysaccharide (LPS) levels. Corticosteroids reduce LPS and
cytokine levels, suggesting that they may improve outcome. A systematic review searching
Embase, MEDLINE and PubMed from the earliest date available until September 2019 was
conducted, according to the PRISMA guidelines, with five papers identified. In four studies,
systemic steroids administered before or at the onset of heat stress improved mortality or
reduced organ dysfunction. Survival time was greatest when steroid administration
preceded heat stress. In one study, a non-significant increase in mortality was seen. A dose
response was observed, with higher doses extending survival time. Animal studies suggest
that steroids improve mortality and/or organ dysfunction after an episode of heat stress or
extreme hyperthermia.
... Although the treatment of cancer with clinical hyperthermia induces direct tumour cell death and the sensitisation of tumours to chemo-and radiotherapeutic strategies [9], regional and whole-body hyperthermia might influence the immune system and mediate protective anti-tumour immune responses [10][11][12][13][14]. This article will summarise the immunological context of the tumour microenvironment with specific reference to adaptive (T cells) and innate (NK cells, macrophages) immune effector cells, and highlight those aspects that have been shown to be influenced by hyperthermia. ...
... Antigen presentation and the induction of adaptive anti-tumour immunity Hyperthermia has been reported to influence all aspects of adaptive anti-tumour immunity, from the function and antigen presentation capacity of APCs, to the responsiveness of CD4 þ and CD8 þ T cell populations [10][11][12][13][14][15]. The influence of hyperthermia on the presentation of tumour-derived antigens to the host immune system can be influenced at the level of antigen expression/release by tumour cells and/or the capacity of APCs to acquire and effectively present antigen to T cells. ...
Much information can be gained by investigating the consequences of hyperthermia on individual cell populations in vitro, however the precise effects of such a therapeutic modality in vivo depend on the tumour microenvironment and the cellular composition therein. Although the direct cytotoxic effects of hyperthermia on tumour tissue can lead to an immediate reduction in tumour volume, long-term benefits to local and distal tumour recurrence will very much depend on the induction of immunity and the capacity of effector cells to traffic to tumours and elicit their cytotoxic functions. The immunological sequelae to hyperthermia are even more important in those instances when large tumour volumes preclude the delivery of appropriate thermal damage. The development of protective anti-tumour immunity requires a plethora of interactions and responses, the vast majority of which can be influenced by temperatures that are consistent with fever-like temperatures (39 degrees -40 degrees C), as well as hyperthermia treatment (<41 degrees C). This article reviews current knowledge relating to the effects of hyperthermia treatment on aspects of the induction and manifestation of immunological responses that are most pertinent to the development and maintenance of protective anti-tumour immunity.
... This result aligns with existing research indicating that hyperthermic conditions applied to the skin can significantly enhance drug delivery and facilitate the penetration of molecules [80]. Mild hyperthermia is also associated with an induced immune effect [81]. The enhancement of drug delivery through the application of hyperthermic conditions to the skin has been a subject of interest in transdermal drug delivery research. ...
The prospective of percutaneous drug delivery (PDD) mechanisms to address the limitations of oral and injectable treatment for rheumatoid arthritis (RA) is increasing. These limitations encompass inadequate compliance among patients and acute gastrointestinal side effects. However, the skin’s intrinsic layer can frequently hinder the percutaneous dispersion of RA medications, thus mitigating the efficiency of drug delivery. To circumvent this constraint, we developed a strontium ranelate (SrR)-loaded alginate (ALG) phototherapeutic hydrogel to assess its effectiveness in combating RA. Our studies revealed that this SrR-loaded ALG hydrogel incorporating photoelectrically responsive molybdenum disulfide nanoflowers (MoS2 NFs) and photothermally responsive polypyrrole nanoparticles (Ppy NPs) to form ALG@SrR-MoS2 NFs-Ppy NPs demonstrated substantial mechanical strength, potentially enabling delivery of hydrophilic therapeutic agents into the skin and significantly impeding the progression of RA. Comprehensive biochemical, histological, behavioral, and radiographic analyses in an animal model of zymosan-induced RA demonstrated that the application of these phototherapeutic ALG@SrR-MoS2 NFs-Ppy NPs effectively reduced inflammation, increased the presence of heat shock proteins, regulatory cluster of differentiation M2 macrophages, and alleviated joint degeneration associated with RA. As demonstrated by our findings, treating RA and possibly other autoimmune disorders with this phototherapeutic hydrogel system offers a distinctive, highly compliant, and therapeutically efficient method.
... Heat stress has been reported to shift the adaptive immune function of the animal from cell-mediated immunity to humoral immunity, which weakens the animal's immune status, increasing the animal's susceptibility to various pathogens (Chauhan et al., 2021). In contrast, there is also an argument that hyperthermia may improve the immune system through hyperthermia-induced changes in cytoskeletal organization and anti-tumor response (Dieing et al., 2007). ...
The primary aim of this investigation was to explore the impact of different temporal stress conditions on the regulators associated with skeletal muscle hypertrophy in bovine myocytes. Bovine satellite cells (BSCs) were extracted from three-month-old Holstein bull calves and subjected to myogenic differentiation under three thermal treatments: 38 °C (control; CON), 39.5 °C (moderate heat stress; MHS), and 41 °C (extreme heat stress; EHS) for a duration of 3 or 48 h. Exposure to EHS resulted in elevated (P < 0.01) expression levels of heat shock protein (HSP)20, HSP27, HSP70, and HSP90, along with increased (P < 0.01) protein levels. Moreover, cells exposed to MHS and EHS exhibited enhanced (P < 0.01) gene expression of myoblast determination protein 1 (MyoD), while myogenin (MyoG) was overexpressed (P < 0.01) in cells exposed to EHS. These findings suggest that heat exposure can potentially induce myogenic differentiation through the modulation of myogenic regulatory factors. Furthermore, our investigations revealed that exposure to EHS upregulated (P < 0.01) myosin heavy chain (MHC) I expression, whereas MHC IIA (P < 0.01) and IIX (P < 0.01) expression were increased; P < 0.01) under MHS conditions. These observations suggest that the temperature of the muscle may alter the proportion of muscle fiber types. Additionally, our data indicated that EHS activated (P < 0.01) the expression of insulin-like growth factor 1 (IGF-1) and triggered the activation of the Akt/mTOR/S6KB1 pathway, a known anabolic pathway associated with cellular protein synthesis. Consequently, these altered signaling pathways contributed to enhanced protein synthesis and increased myotube size. Overall, the results obtained from our current study revealed that extreme heat exposure (41 °C) may promote skeletal muscle hypertrophy by regulating myogenic regulatory factors and IGF-1-mediated mTOR pathway in bovine myocytes.
... The decrease in body temperature also favors the development of an anti-inflammatory profile and immunosuppression, which can act as a double-edged sword depending on the condition [108,[111][112][113]. In the tumoral context, hypothermia provides an immunosuppressive, hence, pro-tumoral microenvironmental due to impaired CD8+ T cell function, an increase of the regulatory and Th2 cells, and higher levels of the cytokines IL-4 and IL-10, which increase cancer progression and metastasis [114][115][116].On the other hand, hyperthermia is recognized to elicit a more robust immune response against infection, injury, and cancer [117]. Several studies reported an increase in IFN-γ and IL-2 secretion from peripheric T cells, enhancement of cytotoxicity, DC maturation, and increase of tumor-specific CD8+ T cells [118][119][120][121]. ...
Adipose tissues are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. Although white adipose tissue and brown adipose tissue are currently considered key endocrine organs, they differ functionally and morphologically. The existence of the beige or brite adipocytes, cells displaying intermediary characteristics between white and brown adipocytes, illustrates the plastic nature of the adipose tissue. These cells are generated through white adipose tissue browning, a process associated with augmented non-shivering thermogenesis and metabolic capacity. This process involves the upregulation of the uncoupling protein 1, a molecule that uncouples the respiratory chain from Adenosine triphosphate synthesis, producing heat. β-3 adrenergic receptor system is one important mediator of white adipose tissue browning, during cold exposure. Surprisingly, hyperthermia may also induce beige activation and white adipose tissue beiging. Physical exercising copes with increased levels of specific molecules, including Beta-Aminoisobutyric acid, irisin, and Fibroblast growth factor 21 (FGF21), which induce adipose tissue browning. FGF21 is a stress-responsive hormone that interacts with beta-klotho. The central roles played by hormones in the browning process highlight the relevance of the individual lifestyle, including circadian rhythm and diet. Circadian rhythm involves the sleep–wake cycle and is regulated by melatonin, a hormone associated with UCP1 level upregulation. In contrast to the pro-inflammatory and adipose tissue disrupting effects of the western diet, specific food items, including capsaicin and n-3 polyunsaturated fatty acids, and dietary interventions such as calorie restriction and intermittent fasting, favor white adipose tissue browning and metabolic efficiency. The intestinal microbiome has also been pictured as a key factor in regulating white tissue browning, as it modulates bile acid levels, important molecules for the thermogenic program activation. During embryogenesis, in which adipose tissue formation is affected by Bone morphogenetic proteins that regulate gene expression, the stimuli herein discussed influence an orchestra of gene expression regulators, including a plethora of transcription factors, and chromatin remodeling enzymes, and non-coding RNAs. Considering the detrimental effects of adipose tissue browning and the disparities between adipose tissue characteristics in mice and humans, further efforts will benefit a better understanding of adipose tissue plasticity biology and its applicability to managing the overwhelming burden of several chronic diseases.
... These processes promote the activation and maturity of antigen-presenting cells (APCs), leading to their differentiation into subtypes, accompanied by the modification of T cell phenotypes. [53][54][55] For example, it has been shown that the differentiation of T lymphocytes into Th2 and regulatory T cells (Tregs) in the spleen can be restrained by heating at 39-40°C; the multiplication of Th1 and Tc1 cells increases under these conditions. 56 Within the human body, Tregs have also been shown to differentiate into Th17 under IL-6 due to hyperthermia. ...
Background:
Within the field of oncotherapy, research interest regarding immunotherapy has risen to the point that it is now seen as a key application. However, inherent disadvantages of immune checkpoint inhibitors (ICIs), such as their low response rates and immune-related adverse events (irAEs), currently restrict their clinical application. Were these disadvantages to be overcome, more patients could derive prolonged benefits from ICIs. At present, many basic experiments and clinical studies using hyperthermia combined with ICI treatment (HIT) have been performed and shown the potential to address the above challenges. Therefore, this review extensively summarizes the knowledge and progress of HIT for analysis and discusses the effect and feasibility.
Methods:
In this review, we explored the PubMed and clinicaltrials.gov databases, with regard to the searching terms "immune checkpoint inhibitor, immunotherapy, hyperthermia, ablation, photothermal therapy".
Results:
By reviewing the literature, we analyzed how hyperthermia influences tumor immunology and improves the efficacy of ICI. Hyperthermia can trigger a series of multifactorial molecular cascade reactions between tumors and immunization and can significantly induce cytological modifications within the tumor microenvironment (TME). The pharmacological potency of ICIs can be enhanced greatly through the immunomodulatory amelioration of immunosuppression, and the activation of immunostimulation. Emerging clinical trials outcome regarding HIT have verified and enriched the theoretical foundation of synergistic sensitization.
Conclusion:
HIT research is now starting to transition from preclinical studies to clinical investigations. Several HIT sensitization mechanisms have been reflected and demonstrated as significant survival benefits for patients through pioneering clinical trials. Further studies into the theoretical basis and practical standards of HIT, combined with larger-scale clinical studies involving more cancer types, will be necessary for the future.
... When HSP70 is liberated to the extracellular electrolyte, it could tumour-specifically carry genetic information and prepare an orchestrated adaptive immune action against the tumour. In general, an induced immune-effect is observed in mild hyperthermia [414], even in preoperative application too [415]. The cytotoxic activity of NK-cells sharply reduces when the temperature growth is to over 41˚C [416] [417], and the general immune activity also drops at over 40˚C [418]. ...
... First, tumor cell-based experiments have confirmed a time-and temperature-dependent cytotoxic effect when temperatures between 41 C and 47 C were applied [5]. The same cell-killing effect is generally assumed in in vivo situations [6]. Moreover, several clinical studies underlined the importance of duration and extent of supranormal temperature achieved during thermal treatment [7,8]. ...
Aim: In oncology, thermal therapy is the application of external heat to fight cancer cells. The goal of whole-body thermal treatment (WBTT) is to raise the patient’s core temperature to 39–42 °C, and represents the only thermal treatment modality that can act on both the primary tumor and distant metastases. However, WBTT carries potential risks for toxicity when applied without accurate thermometry and monitoring.
Methods: ElmediX has developed a medical device, HyperTherm, to deliver long-term controlled and accurate WBTT (41.5 °C, up to 8 h). The safety of the device and thermal treatment protocol was initially evaluated in minipigs, and we present the confirmation of tolerability of WBTT in dogs with advanced cancer, in combination with a reduced dose of radiotherapy or chemotherapy.
Results: Thermometry in liver, rectum, and tumor confirmed a homogeneous heating of these body parts. Monitoring of clinical parameters showed acceptable and reversible changes in liver, cardiac, muscle and coagulation parameters, as was expected. Combination of WBTT with both radiotherapy and chemotherapy only caused some low-grade adverse events.
Conclusion: We conclude that our findings support the safe use of HyperTherm-mediated WBTT for canine patients with advanced malignancies. They also tend to support a genuine therapeutic potential for long-term WBTT which needs to be confirmed on a larger dog patient population. Combined with previously reported safety results in minipigs, these contribute to support the ongoing clinical evaluation of WBTT in advanced human cancer patients.
... First, tumor cell-based experiments have confirmed a time-and temperature-dependent cytotoxic effect when temperatures between 41 C and 47 C were applied [5]. The same cell-killing effect is generally assumed in in vivo situations [6]. Moreover, several clinical studies underlined the importance of duration and extent of supranormal temperature achieved during thermal treatment [7,8]. ...
In oncology, thermal therapy is the application of external heat to fight cancer cells. The goal of whole-body thermal treatment (WBTT) is to raise the patient’s core temperature to 39-42°C, and represents the only thermal treatment modality that can act on both the primary tumor and distant metastases. However, WBTT carries potential risks for toxicity when applied without accurate thermometry and monitoring. ElmediX has developed a medical device, HyperTherm, to deliver long-term controlled and accurate WBTT (41.5°C, up to 8 h). The safety of the device and thermal treatment protocol was initially evaluated in minipigs, and we present the confirmation of tolerability of WBTT in dogs with advanced cancer, in combination with a reduced dose of radiotherapy or chemotherapy. Thermometry in liver, rectum, and tumor confirmed a homogeneous heating of these body parts. Monitoring of clinical parameters showed acceptable and reversible changes in liver, cardiac, muscle and coagulation upon WBTT. Combination of WBTT with both radiotherapy and chemotherapy only caused some low-grade adverse events. We conclude that our findings support the safe use of HyperTherm-mediated WBTT for canine patients with advanced malignancies. They also tend to support a genuine therapeutic potential for long-term WBTT which needs to be confirmed on a larger dog patient population. Combined with previously reported safety results in minipigs, these contribute to support the ongoing clinical evaluation of WBTT in advanced human cancer patients.
... Additionally, the increase of the local or systemic temperature may enhance the sensitivity of cancer cells to chemotherapeutic drugs, modulate immunity, and quicken apoptosis of tumor cells. 5,6 Therefore, thermosensitive drug delivery systems are particularly explored for application in cancer therapy. Poly(N-isopropylacrylamide) (PNIPAAm) is the most frequently used polymer for the preparation of thermo-sensitive SDDS due to its phase transition temperature (lower critical solution temperature, LCST), which is close to the physiological temperature of human body. ...
Purpose
Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems.
Methods
A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol–1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated.
Results
Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system.
Conclusion
The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.
... It was observed that the cytotoxicity of NK-cells sharply drops above 41 • C (391,392), and the activity of the immune-cells decreases. However, in the mild range an induced immune-effect is observed (393), even in the preoperative application (394). The suppression of the immuneactivity by the high local tumor-temperature in LRHT is often neglected, with an assumption that new immune cells from the non-heated areas will be delivered. ...
Heating as a medical intervention in cancer treatment is an ancient approach, but effective deep heating techniques are lacking in modern practice. The use of electromagnetic interactions has enabled the development of more reliable local-regional hyperthermia (LRHT) techniques whole-body hyperthermia (WBH) techniques. Contrary to the relatively simple physical-physiological concepts behind hyperthermia, its development was not steady, and it has gone through periods of failures and renewals with mixed views on the benefits of heating seen in the medical community over the decades. In this review we study in detail the various techniques currently available and describe challenges and trends of oncological hyperthermia from a new perspective. Our aim is to describe what we believe to be a new and effective approach to oncologic hyperthermia, and a change in the paradigm of dosing. Physiological limits restrict the application of WBH which has moved toward the mild temperature range, targeting immune support. LRHT does not have a temperature limit in the tumor (which can be burned out in extreme conditions) but a trend has started toward milder temperatures with immune-oriented goals, developing toward immune modulation, and especially toward tumor-specific immune reactions by which LRHT seeks to target the malignancy systemically. The emerging research of bystander and abscopal effects, in both laboratory investigations and clinical applications, has been intensified. Our present review summarizes the methods and results, and discusses the trends of hyperthermia in oncology.
... It was observed that the cytotoxicity of NK-cells sharply drops above 41 • C (391,392), and the activity of the immune-cells decreases. However, in the mild range an induced immune-effect is observed (393), even in the preoperative application (394). The suppression of the immuneactivity by the high local tumor-temperature in LRHT is often neglected, with an assumption that new immune cells from the non-heated areas will be delivered. ...
Hyperthermia was the very first oncotherapy in human medicine, but its applicability in modern oncology was dubious. The discovery of electromagnetism gave new hope a century ago, however, until up to now, it has been suffering from lack of wide acceptance. Oncological hyperthermia suffers from multiple unsolved medical and technical problems. The accurate selection of malignant tissue and its proper heating in depth are real challenges together with the control and repeatability of the treatments. However, the center of the problems is not technical: the living system tries to keep its homeostatic equilibrium and creates active feedback mechanisms to eliminate or at least correct the constrain heating in depth. The proper reaction on the “gage of battle” has to involve the physiology, handle it complexly together with bio-electromagnetism and update connected technology. The solution has to be the integration of the natural bio-effects into the technological constrains, acting in synergy with the physiological feedback mechanisms, and without forcing effects out of the homeostatic control. The solution lies in strict selection and adequate action in nanoscopic range, without exciting the robust transport-mechanisms to operate against the energy delivery to the tumor. Together with the local optimization, the systemic effects have to be considered, because malignancy is not a local disease. This concept needs interactions with the immune-system being effective on the disseminated cell in far distance too. Our objective is to present a complex technical solution to this complex problem.
... It was observed that the cytotoxicity of NK-cells sharply drops above 41 • C (391,392), and the activity of the immune-cells decreases. However, in the mild range an induced immune-effect is observed (393), even in the preoperative application (394). The suppression of the immuneactivity by the high local tumor-temperature in LRHT is often neglected, with an assumption that new immune cells from the non-heated areas will be delivered. ...
The next generation of oncological hyperthermia involves the medical innovation of selectively heating up the malignant cells of the body in a controlled way. The easily-distinguishable biophysical and physiological characteristics of cancer cells and their immediate environment are the focus of the targeted energy delivery of this treatment. This heterogenic heating concept breaks with the homogeneous nature of conventional hyperthermia, where an isothermally equal temperature is applied to the large surface area of a solid tumor. Due to its selectivity, the new concept enables the usage of a significantly lower energy, making it safer, less toxic, and easier to use.
This book shows the challenges facing oncological hyperthermia, and highlights clinical results obtained in various countries. It also presents discussions about the theoretical basis of the method, adding some technical discussions and clarifying the most difficult points of its design. The contributions dealing with clinical results use state-of-art conventional therapies with complementary hyperthermia and show the advantages of such a combination.
... Compared to more pronounced suppression of tumor growth in prior studies 1,3,43 , MFH effects seen in this study were more modest. This was likely due to a relatively low specific absorption rate of ferumoxytol compared to other SPIOs 31 , a delivery of small injection volume into the tumor, and the use of immune-compromised host that lacks in a hyperthermia-induced immune or macrophage-mediated killing of tumors 44,45 . It is also likely that further optimization including ferumoxytol dose, route of injection, timing of injection and AMF application, and AMF parameters will significantly influence the efficiency of tumor killing. ...
The use of magnetic fluid hyperthermia (MFH) for cancer therapy has shown promise but lacks suitable methods for quantifying exogenous irons such as superparamagnetic iron oxide (SPIO) nanoparticles as a source of heat generation under an alternating magnetic field (AMF). Application of quantitative susceptibility mapping (QSM) technique to prediction of SPIO in preclinical models has been challenging due to a large variation of susceptibility values, chemical shift from tissue fat, and noisier data arising from the higher resolution required to visualize the anatomy of small animals. In this study, we developed a robust QSM for the SPIO ferumoxytol in live mice to examine its potential application in MFH for cancer therapy. We demonstrated that QSM was able to simultaneously detect high level ferumoxytol accumulation in the liver and low level localization near the periphery of tumors. Detection of ferumoxytol distribution in the body by QSM, however, required imaging prior to and post ferumoxytol injection to discriminate exogenous iron susceptibility from other endogenous sources. Intratumoral injection of ferumoxytol combined with AMF produced a ferumoxytol-dose dependent tumor killing. Histology of tumor sections corroborated QSM visualization of ferumoxytol distribution near the tumor periphery, and confirmed the spatial correlation of cell death with ferumoxytol distribution. Due to the dissipation of SPIOs from the injection site, quantitative mapping of SPIO distribution will aid in estimating a change in temperature in tissues, thereby maximizing MFH effects on tumors and minimizing side-effects by avoiding unwanted tissue heating.
... Numerous studies suggest synergy between hyperthermia-inducing strategies and immune-based platforms, which share a common origin in the cancer vaccine work [8]. Anti-tumor immunity is heightened by several thermally induced mechanisms, including NK and T-cell ligand expression by tumor cells, increased antigen chaperoning by heat shock proteins, tumor cell exosome release, direct activation of infiltrating lymphocytes and improved vascular permeability [9]. ...
Brain tumors present unique therapeutic challenges and they include glioblastoma (GBM) and metastases from cancers of other organs. Current treatment options are limited and include surgical resection, radiation therapy, laser interstitial thermal therapy and chemotherapy. Although much research has been done on the development of immune-based treatment platforms, only limited success has been demonstrated. Herein, we demonstrate a novel treatment of GBM through the use of plasmonic gold nanostars (GNS) as photothermal inducers for synergistic immuno photothermal nanotherapy (SYMPHONY), which combines treatments using gold nanostar and laser-induced photothermal therapy with checkpoint blockade immunotherapy. In the treatment of a murine flank tumor model with the CT-2A glioma cell line, SYMPHONY demonstrated the capability of producing long-term survivors that rejects rechallenge with cancer cells, heralding the successful emergence of immunologic memory. This study is the first to investigate the use of this novel therapy for the treatment of GBM in a murine model.
... Immune cells must be protected to maintain lymphocyte function impaired by HT. Lymphocyte apoptosis increases and thereby ameliorates the immune response under the high temperature stress [15]. In the present study, a 44 °C water bath was used to simulate an extreme HT condition, and the U937 cell line was used as a model of lymphocytes. ...
Dihydromyricetin (DMY) is a traditional herbal medicine, with a wide range of biological activities. Extreme hyperthermia (HT) can suppress the immune system; thus, protection of the immune system is beneficial in heat-related diseases, including heatstroke. In our study, we revealed the protective effect of DMY against HT-induced apoptosis and analysed the underlying molecular mechanisms. We incubated human myelomonocytic lymphoma U937 cells at 44 °C for 30 min with or without DMY and followed by further incubation for 6 h at 37 °C. Cell viability was determined by the CCK-8 assay. DMY did not cause any cytotoxic effects in U937 cells even at high doses. HT treatment alone induced significant apoptosis, which was detected by DNA fragmentation and Annexin V/PI double staining. Mitochondrial dysfunction was identified by loss of mitochondrial membrane potential (MMP) during heat stimulation. Apoptotic related proteins were involved, truncated Bid and caspase-3 were upregulated, and Mcl-1 and XIAP were downregulated. We also identified the related signalling pathways, such as the MAPK and PI3K/AKT pathways. However, changes in HT were dramatically reversed when the cells were pretreated with DMY before exposure to HT. Overall, MAPKs and PI3K/AKT signalling, mitochondrial dysfunction, and caspase-mediated pathways were involved in the protective effect of DMY against HT-induced apoptosis in U937 cells, which was totally reversed by DMY pretreatment. These findings indicate a new clinical therapeutic strategy for the protection of immune cells during heatstroke.
... Sometimes the terms mild hyperthermia or just hyperthermia is used for temperatures up to 42 • C and extreme hyperthermia for higher temperatures [23]. At those temperatures, heat alone may cause protein denaturation [24], damage to the cytoskeleton [25,26], impairment of certain DNA repair processes [27][28][29][30][31][32], changes in cell membrane permeability [33,34], and stimulation of the immune system [35][36][37][38]. ...
Hyperthermia, though by itself generally non-curative for cancer, can significantly increase the efficacy of radiation therapy, as demonstrated by in vitro, in vivo, and clinical results. Its limited use in the clinic is mainly due to various practical implementation difficulties, the most important being how to adequately heat the tumor, especially deep-seated ones. In this work, we first review the effects of hyperthermia on tissue, the limitations of radiation therapy and the radiobiological rationale for combining the two treatment modalities. Subsequently, we review the theory and evidence for magnetic hyperthermia that is based on magnetic nanoparticles, its advantages compared with other methods of hyperthermia, and how it can be used to overcome the problems associated with traditional techniques of hyperthermia.
... Un chauffage et un effet quasi sélectif sur les cellules de la tumeur peut même être obtenu quand les tissus ciblés renfermant la lésion sont chauffés entre 40 et 44°C [146]. Ainsi, quand l'hyperthermie est conçue comme agent sensibilisant à d'autres thérapies, dans le cadre de protocoles modernes du traitement des tumeurs recourant à de multiple thérapies et modalités, cet effet de chauffage différentiel s'associe avec un gain thérapeutique substantiel et très profitable [6,10,38,147,148]. Des essais cliniques avec l'association hyperthermie et radiations ionisantes ont bien établi le potentiel radiosensibilisateur de l'hyperthermie [6]. ...
Dans ce travail, nous passons en revue les efforts de formulation et de préformulation pharmaceutiques pertinentes pour les nouvelles modalités d'hyperthermie magnétiquement induite dans le traitement des lésions cancéreuses pour lesquelles une thermothérapie est indiquée, ou pour des indications de novo dans certaines situations cliniques. Nous introduirons d'abord les principes biologiques généraux sousjacentsà l'utilisation de l'hyperthermie, compte tenu des moyens techniques pour générer l'hyperthermie actuellement accessibles, nous détaillerons plus précisément différentes modalités magnétiques de chauffage. Nous présenterons alors une synthèse des formulations décrites dans la littérature, en comparant leurs spécificités, avantages et inconvénients. Premièrement, nous considérerons les biomatériaux basés sur les céramiques, les verres et les ciments, pour hyperthermie à médiation magnétique dans le traitement des tumeurssolides de l'os, tenant compte de ses spécificités biologiques. Dans un deuxième temps seront considérées les formulations destinées à l'induction magnétique d'une hyperthermie localisée pour le traitement de tumeurs solides des tissus mous, en insistant sur les modulations biochimiques et pharmacologiques. Dans la dernière partie, nous considérerons les formulations de liposomesmagnétiques qui peuvent être également administrées dans divers types de tumeurs. Nous n'avons pas détaillé ici les formulations magnétiques pour l'hyperthermie magnétique fluide qui sont basées sur l'administration de suspensions de nanoparticules magnétiques stabilisées par un revêtement de surface permettant des applications biologiques.Les importantes considérations biologiques et immunologiques qui sont associés à ces formulations seront décrites. En tout point, cette revue se concentrera sur l'importance de la formulation pharmaceutique et sur les interactions extrêmement complexes en lien avec l' hyperthermie qui devraient être pris en compte dans diverses applications médicales.
... It was reported that the cells undergo a "rapid mode of cell death" when they are exposed to heat (hyperthermia or heating environments) 19 . In addition, it was observed that hyperthermia can induce microscopically detectable damage to the mitotic apparatus 6,19,20 . This damage results in inefficient mitosis and consecutive polyploidy. ...
In this study, we investigated the effects of recovery time during magnetic nanofluid hyperthermia (MNFH) on the cell death rate and the heat shock proteins 72 (HSP72) induction behavior in retinal ganglion cells (RGCs-5) to provide a possible solution for highly efficient ocular neuroprotection. The recovery time and the heat duration time during MNFH were systematically controlled by changing the duty cycle of alternating current (AC) magnetic field during MNFH. It was clearly observed that the cell death rate and the HSP72 induction rate had a strong dependence on the recovery time and the optimizated recovery time resulted in maximizing the induction efficiency of HSP72. Controlling the recovery time during MNFH affects not only the cell death rate but also HSP72 induction rate. The cell death rate after MNFH was dramatically decreased by increasing the recovery time during MNFH. However, it was also found that the HSP72 induction rate was slightly decreased by increasing the recovery time. These results indicate that applying the appropriate or optimized recovery time during MNFH can improve the induction efficiency of HSP72 by minimizing the cell death caused by cytotoxic effects of heat.
... Although the role of HSPs is still under investigation, current evidence has proved that enhanced immunogenicity and HSP expression seen after tumor cells are heated, thermally enhanced immune effector cell activation and function, thermally enhanced vascular perfusion and delivery or trafficking of immune effector cells to tumors (10,11). Due to their unique immunologic features, HSPs are induced by hyperthermia known as specific immunogenic effectors (12,13). To regard as many Studies that have demonstrated immunological effects of fever range whole-body hyperthermia (FR-WBH), The most important role of elevation temperature in fever range is immunological effects. ...
Hyperthermia refers to elevation tumor temperature from 39 up to 43 degree Celsius. Actually Therapeutic Hyperthermia has been used as an adjuvant treatment for cancer, since end of the 19th century after observations William Coley who found that tumor is diminished after induction of fever by bacterial toxins. Hyperthermia therapy refers to treatment tumors through heating which has been used since the time of the ancient Egyptians. The term ‘Hyperthermia’ in oncology means treatment of malignant disease by heating in different ways. Hyperthermia is usually applied as an adjuvant therapy method in combination with other modalities such as Radiotherapy or Chemotherapy in cancer treatment. Typically there are three categories for Hyperthermia, including local, regional and whole body. Based on the temperature Whole body hyperthermia classify in 3 type, mild, fever range and extreme. In Mild hyperthermia, the temperature is from 37.5 up to 38.5 degree Celsius, in fever range hyperthermia, 38.5 up to 40 degree Celsius, and extreme hyperthermia, the temperature above 40 degree Celsius. Now Days Whole body hyperthermia known as immunotherapy related to cancer treatment in oncology. Here we will review whole body hyperthermia related to cancer treatment.
... Molecular effectors of hyperthermia include; Cell membrane Alterations in fluidity, stability, Changes in structure; stability of plasma membrane, membrane potential, cell surface receptors, transmembrane transport mechanisms, apoptosis, Impairment of ion transport (Ca2+, Na+, Mg+, K+); Impairment of protein synthesis, Induction of HSP synthesis, Generation of reactive oxygen species (ROS), Impairment of RNA/DNA synthesis, inhibition of DNA-repair mechanisms, Modification of gene expression, signal transduction Inhibition of DNA repair enzymes, and Protein synthesis (impaired), miss folding, denaturation /nuclear aggregation (7)(8)(9)(10).Although the role of HSPs is still under investigation, current evidence has proved that enhanced immunogenicity and HSP expression seen after tumor cells are heated, thermally enhanced immune effector cell activation and function, thermally enhanced vascular perfusion and delivery or trafficking of immune effector cells to tumors (11,12). Due to their unique immunologic features, HSPs are induced by hyperthermia known as specific immunogenic effectors (13,14). It is now appreciated that heating tumors( in situ ) can activate vascular, metabolic, and immunologic parameters of the tumor microenvironment which may play an additional role in radiochemosensitization beyond hyperthermia induced cell killing of tumor cells (15,16). ...
... Today, hyperthermia is almost always used with other forms of cancer therapies as it provides a possibility for synergy with different actions of conventional therapies. (117) ...
Cancer is a class of diseases characterized by out of control cell growth. There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected. Cancer is a potentially fatal genetic disease that is caused mainly by environmental factors. The cancer causing agents (carcinogens) can be present in food & water, in the air, in chemicals and sunlight that people are exposed to. Cancer begins when cells in a part of the body start to grow out of control. Cancer cell growth is different from normal cell growth. Instead of dying, cancer cells continue to grow and form new abnormal cells. Cancer cells can also invade other tissues. Growing out of control and invading other tissues are what makes a cell a cancer cell. Humans have been fighting against cancers past hundreds years. During that period, many clinical modalities have been proposed to treat cancers. Among them, the clinical procedures known as cryosurgery and hyperthermia.
Cryosurgery employs very low temperatures (freezing) to destroy undesirable and diseased tissues, in order to kill it. Applications of this treatment are used quite widely in superficial diseases such as tumors, warts and some other dermatological conditions. The advantages of cryosurgery treatment are minimally invasive, repeatable, has less side effects and can be operated at different targets in the same organ at the same time.
Hyperthermia may be defined more precisely as raising the temperature of a part of or the whole body above normal for a defined period of time. The extent of temperature elevation associated with hyperthermia is on the order of a few degrees above normal temperature (41 - 45°C). Because of the results that high temperature may produce in tissues, one can refer to use of temperatures (>50°C) as coagulation, (60 to 90°C) as thermal ablation and (>200°C) as charring. Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures, using external and internal heating devices. Hyperthermia is almost used with other forms of cancer therapy such as radiation and chemotherapy. Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues. It is proposed that by killing cancer cells and damaging proteins and structures within the cells, hyperthermia may shrink tumors making the cells more sensitive to radiation therapy (RT) or chemotherapy.
The aim of present study, design and construct a Cryosurgery-Hyperthermia device using thermoelectric effect using simple national materials. This device was used to destroy a superficial tumor and to study the effect of the combined cryosurgery and hyperthermia treatments using Peltier effect on the malignant tissues.
Cryosurgery-Hyperthermia device was constructed and developed. The constructed device consists of the following four main parts: power supply, freezing-heating system, thermometer and controlling part. The freezing-heating system is the most important part of device that actually produces freezing and heating, which consists of freezing-heating head, thermoelectric (Peltier) module, heat sink and water pump. The freezing-heating head designed to meet a wide range of heating and freezing needs to quicker and less invasive treatment for some cancer patients. The freezing-heating head contacts with a thermoelectric (Peltier) module coupled to a water flow based heat sink, which dissipates heat to water when the head is cooled and absorbs heat from water while the head is heated. The polarity of the DC power supply can be reversed by the switch to achieve the conversion between freezing and heating mode.
The present work was carried out in 60 male Swiss albino mice injected with (2 x 106) Ehrlich ascites carcinoma cells, mammary in origin, diluted approximately (1-4) in 0.9% saline. A week later, the tumor reached approximately a size of about 0.5-1 cm in diameter. The tumor bearing mice were divided into five main groups:
Group 1 deals as control (20 mice): mice bearing tumor without treatment.
Group 2 (10 mice): mice bearing tumor exposed to cryosurgery treatment at –20°C for 5 minutes followed by hyperthermia treatment at 45°C for 5 minutes every day for 10 days.
Group 3 (10 mice): mice bearing tumor exposed to cryosurgery treatment at –20°C for 7.5 minutes followed by hyperthermia treatment at 45°C for 7.5 minutes every day for 10 days.
Group 4 (10 mice): mice bearing tumor exposed to cryosurgery treatment at –20°C for 10 minutes followed by hyperthermia treatment at 45°C for 10 minutes every day for 10 days.
Group 5 (10 mice): mice bearing tumor exposed to cryosurgery treatment at –20°C for 12.5 minutes followed by hyperthermia treatment at 45°C for 12.5 minutes every day for 10 days.
For all groups, the length and width of the tumor were measured every day with a slide caliper before subjected to Cryosurgery-Hyperthermia therapy and tumor growth volume was calculated. At the end of ten days, all animals were killed and the tumors were dissected out, their volumes were measured. Tumor volume inhibition ratio was calculated.
In the present work dielectric measurements were performed on control group (untreated), group 3 exposed to cryosurgery treatment at –20°C for 7.5 minutes followed by hyperthermia treatment at 45°C for 7.5 minutes and Group 4 exposed to cryosurgery treatment at –20°C for 10 minutes followed by hyperthermia treatment at 45°C for 10 minutes every day for 10 days.
The Experimental Results Showed That:
• A homemade Cryosurgery-Hyperthermia device was developed and constructed with simple and available materials. By examining the constructed cryosurgery-hyperthermia device, we found a device can easily reach (–20°C) during freezing and above (100°C) during heating.
• It showed that the combination treatment of both cryosurgery and hyperthermia therapies were effective to destroy the tumors by exposed with freezing and heating energy at different treatment conditions and the higher temperature applied immediately after freezing might reinforce the tumor destruction.
• Tumor growth rate increases in untreated control group. Tumor growth rate decreased in treated group with cryosurgery and hyperthermia therapy.
• A clear inhibition ratio in tumor volume was observed in treated group than untreated.
• Dielectric measurements performed on control group (untreated), group 3 and group 4 showed variation in real conductivity with frequency, the imaginary and real conductivity, the relative permittivity with frequency and the imaginary and relative permittivity between untreated and treated groups, using cryosurgery and hyperthermia therapy with different exposure times.
• Dielectric measurements can be used to monitor the changes that occur in cells due to the Cryosurgery-Hyperthermia therapy
... The nuclear matrix shows damage at lower temperatures than other parts of the cell, with significant endothermic changes observed at 40°C [37]. Direct cell death in humans occurs at temperatures of Taken from [23] with permission around 41°C, with the rate of cell death increasing markedly with even modest further increases in temperature [36,38]. The thermal energy required for cell death is similar to that required for protein denaturation, suggesting that hyperthermic cell death may occur primarily through its effect on protein structure, although cell death occurs primarily through necrosis or from apoptosis depending on the cell line and the temperature [36]. ...
There are numerous causes of a raised core temperature. A fever occurring in sepsis may be associated with a survival benefit. However, this is not the case for non-infective triggers. Where heat generation exceeds heat loss and the core temperature rises above that set by the hypothalamus, a combination of cellular, local, organ-specific, and systemic effects occurs and puts the individual at risk of both short-term and long-term dysfunction which, if severe or sustained, may lead to death. This narrative review is part of a series that will outline the pathophysiology of pyrogenic and non-pyrogenic fever, concentrating primarily on the pathophysiology of non-septic causes.
... In accordance, whole body hyperthermia combined with chemotherapy induces a strong but reversible anti-inflammatory stress response in cancer patients during therapy [1]. Therapeutical hyperthermia might activate the immune system in a reproducible manner and influence positively the course of diseases [16]. However, heat stress over 41°C of body temperature is also associated with lymphopenia [9] and with lymphocyte apoptosis [17]. ...
Acute exercise induces changes in peripheral mononuclear cells' (PBMCs) capabilities to produce cytokines. The aim was to investigate the effect of docosahexaenoic acid (DHA) diet supplementation on cytokine production, by lipopolysaccharide (LPS)-stimulated PBMCs after exercise, and the in vitro influence of temperature. Fifteen male soccer players were randomly assigned to a placebo or an experimental group. The experimental group consumed an almond-based beverage enriched with DHA (1.16 g DHA/day) for 8 weeks, whereas the placebo group consumed a similar non-enriched beverage. Blood samples were taken before and after the nutritional intervention in basal conditions and 2 h after acute exercise. Nutritional intervention significantly increased the DHA content in erythrocytes only in experimental group (from 34 ± 3.6 to 43 ± 3.6 nmols DHA/10(9) erythrocytes). Exercise significantly increased Toll-like receptor 4 (TLR4) in PBMCs but only in the placebo group (203 %). Exercise also significantly increased IL6, IL8, VEGF, INFγ, TNFα, IL1α, IL1β, MCP1, and EGG production rates by LPS-stimulated PBMCs, and this response was attenuated by DHA supplementation. Temperature but not DHA also affected the pattern of cytokine production increasing IL6, IL8, IL1β, and MCP1 synthesis. The higher change was evidenced in IL1β increasing the production rate at 39.5 °C from 3.19 ± 0.77 to 22.4 ± 6.1 pg/h 10(6) PBMC in placebo and from 2.36 ± 0.11 to 10.6 ± 0.38 pg/h 10(6) PBMC in the supplemented group. The profile of affected cytokines differs between temperature and exercise, suggesting a different PBMC activation pathway. DHA diet supplementation only attenuated cytokine production after exercise and not that induced by temperature.
... Several mechanisms of action by which hyperthermia augments irradiation have been investigated. These mechanisms include radiosensitising effects by inhibition of DNA repair, immuno-stimulatory effects, increased perfusion, and therefore improved oxygenation of hypoxic tissues and direct cell death [6][7][8][9]. Yet clinical data for the combination of hyperthermia with RCT in rectal cancer is rare [10][11][12]. ...
Purpose:
The aim of this study was to evaluate the impact of deep regional hyperthermia on long-term local control and survival in locally advanced non-metastatic rectal cancer.
Methods:
In total 103 patients with locally advanced non-metastatic rectal cancer were treated preoperatively with either neoadjuvant radiochemotherapy alone (n = 43) or the same treatment with additional deep regional hyperthermia (n = 60). The two groups were compared with respect to local control, overall survival (OS), disease-free survival (DFS), and distant metastases-free survival (DMFS).
Results:
Patients receiving additional hyperthermia had excellent long-term local control with a 5-year Kaplan-Meier estimate of 98% compared with 87% in the radiochemotherapy only group (p = 0.09). Five-year rates for OS (88% versus 76%, p = 0.08), DFS (77% versus 73%, p = n.s.) and DMFS (75% versus 77%, p = n.s.) were not statistically different between the two groups.
Conclusion:
Radiochemotherapy combined with hyperthermia results in excellent long-term local control.
... Un chauffage et un effet quasi sélectif sur les cellules de la tumeur peut même être obtenu quand les tissus ciblés renfermant la lésion sont chauffés entre 40 et 44°C [146]. Ainsi, quand l'hyperthermie est conçue comme agent sensibilisant à d'autres thérapies, dans le cadre de protocoles modernes du traitement des tumeurs recourant à de multiple thérapies et modalités, cet effet de chauffage différentiel s'associe avec un gain thérapeutique substantiel et très profitable [6,10,38,147,148]. Des essais cliniques avec l'association hyperthermie et radiations ionisantes ont bien établi le potentiel radiosensibilisateur de l'hyperthermie [6]. ...
In this work, we review the advances to obtain pharmaceutical formulations relevant for the recent magnetically mediated modality of hyperthermia treatment of cancer lesions, mainly solid tumors. We introduce in the first part biological rationales with respect to the technical means presently implemented in clinics for hyperthermia treatment, focusing on magnetically mediated modalities. We will then discuss the potential of the pharmaceutical formulation gathered. In the second part, we will consider biomaterials based on ceramics, glasses and cements that are indicated in the hyperthermia treatment of solid bone tumors by magnetically mediated modality, taking pathophysiological particularities in account. In the third part, we will present the formulations for the hyperthermic treatment of solid tumors of soft tissue by magnetically induced modalities, insisting on pharmacological and biochemical modulations. The fourth and last part is dedicated to liposomes formulations, centrally on magneto-liposomes that can be administrated in various tumor in view of magnetically mediated hyperthermia. We cannot detail here the magnetic fluid formulations, consisting in suspension of coated magnetic nanoparticles. The important biological and immunological considerations will be thoroughly considered. This review will emphasize the extremely complex but central interactions in link with hyperthermia that should be considered for clinical application.
... Quasiselective damage of the tumor lesion can be achieved by regional or local heating to temperature between 40 and 44°C [145]. Moreover, when hyperthermia is used as a sensitizing agent to additional therapies in multi modality approaches, the differential heating effect is of first importance in terms of therapeutic gain [5,9,37,146,147]. Clinical studies of the association of hyperthermia with ionizing radiation have established the potential of heat in radiosensitization [5]. ...
In this thesis work, injectable formulations forming in-situ an implant that entraps superparamagnetic microparticles are developed in view of treating solid tumors by inducing magnetically a local moderate hyperthermia. We first review physical, biological and clinical aspects of induced hyperthermia for cancer treatment, emphasizing electro-magnetic modalities. The in vitro and in vivo investigations of materials and their formulation is then presented. In the next chapter, we characterize the physico-chemical, magnetic and heating properties under an alternating magnetic field (115 kHz, 9 - 12 mT) of silica microparticles embedding superparamagnetic iron oxide nanoparticles (SPIONs) and of selected formulations thereof: an alginate hydrogel and an organogel oof poly(ethylene-co-vinyl alcohol) in dimethysulfoxide). Finally, we demonstrate the therapeutic potential of the superparamagnetic injectable organogel to treat subcutaneous necrotizing solid tumors of human colocarcinoma in a murine model by 20-min magnetic induction of local hyperthemia.
... Also, increased temperature may slow down or even block DNA replication (Xu et al., 2007) or inhibits cellular repair mechanisms (Krawczyk et al., 2011), denature proteins, and inhibit angiogenesis (Dahl et al., 2008). Hyperthermia has been shown to induce heat-shock proteins (Ciocca et al., 2010;Jolescha et al., 2011) and stimulate the immune system (Calderwood et al., 2005;Dieing et al., 2007;Peer et al., 2010) with observed increases in natural killer cell activity (Dayanc et al., 2008). Lymphocytes, which are encountered in large numbers both in the blood as well as between the body cells, would be more reactive due to the increased temperature. ...
Hyperthermia is a therapeutic procedure used to raise the body or local tissue temperature to about 41-43°C through the application of electromagnetic or ultrasound energy for a defined period of time to sensitize cells for additional therapies. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centers worldwide. Hyperthermia is almost always used with other forms of cancer therapies as it provides a possibility for synergy with different actions of conventional therapies. Hyperthermia in combination with radiotherapy and/or chemotherapy results in higher response rates, accompanied by improved local tumor control rates, better palliative effects and/or better overall survival rates in selected cases of tumor types. Significant improvement in clinical outcome has been demonstrated for tumors of the bladder, breast, cervix, head and neck, and soft tissue sarcomas. In this article, background information on the biological rationale for the application of hyperthermia to human cancer treatment, an overview of technologies and a summary of clinical outcomes published since 2005 are provided.
... The same inherent tumor characteristics (hypoxia, acidic pH, and poor nutrition) that result in the reduced response of tumors to radiation and chemotherapy actually render tumor cells more susceptible to hyperthermia [16] . Because of the connection between fever and immunological reactions, it has also been suggested that hy-perthermia treatment may activate the immune system against the tumor [19] . Moreover, in tumor but not normal cells, the heat triggered heat shock proteins translocate to the cell membrane where they act as receptors for natural killer cells, macrophages, and antigen-presenting cells, thus contributing to the observed cytotoxic effect of hyperthermia on cancer cells [20] . ...
Currently there are no tumor-specific superparamagnet-ic iron oxide (SPIO) nanocomplexes on the market for use as either diagnostic or hyperthermic agents. Moreover, none of the current hyperthermia approaches can effi-ciently treat disseminated (metastatic) cancer. Our anti-transferrin receptor scFv immunoliposome (scL) is a sys-temically administered, tumor-targeting nanocomplex for molecular medicines. It efficiently and specifically de-livers various payloads to tumor cells in vivo and has suc-cessfully completed a phase I clinical trial for p53 gene therapy. We modified this scL complex to encapsulate SPIO. We have demonstrated that the scL nanocomplex can deliver SPIO specifically and efficiently into tumor cells, resulting in tumor growth inhibition in vivo. Thus, scL-SPIO should be capable of delivering sufficient SPIO to generate therapeutic temperatures only in the tumor when the patient is exposed to an alternating magnetic field. As SPIO is also used in MRI, use of scL-SPIO would allow simultaneous imaging and hyperthermic treat-ment. This scL-SPIO nanocomplex theranostic agent has the potential to simultaneously diagnose metastatic tu-mors, act as a therapeutic, and assess the treatment ef-fect while minimizing heat effects on normal cells. Thus, it could have a significant clinical impact on the treat-ment of cancer, including metastatic lung cancer.
... Quasi-selective damage of the tumor lesion can be achieved by regional or local heating to temperature between 40 and 44°C [145]. Moreover, when hyperthermia is used as a sensitizing agent to additional therapies in multi-modality approaches, the differential heating effect is of first importance in terms of therapeutic gain [5,9,37,146,147]. Clinical studies of the association of hyperthermia with ionizing radiation have established the potential of heat in radiosensitization [5]. ...
In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue solid tumors, emphasizing the potential for pharmacological modulation. In the final section, we consider magnetic liposome formulations that can be equally administrated in various types of tumors. We do not detail magnetic fluid hyperthermia that uses suspensions of magnetic nanoparticles stabilized by various coatings. Biological and immunological considerations revealed by liposomes are outlined. This chapter focuses on the importance of the formulation and on
the highly complex interactions between formulation and hyperthermia that should be considered with respect to various medical applications.
... Heat-stroke or severe heat stress characterized by hyperthermia results in elevations of cytokines, such as interleukin 1 (IL-1), tumor necrosis factor alpha (TNF alpha) and blood coagulation, and changes in immune responses (Villar et al. 1994;Bouchama et al. 1991;O'Donnell 1975). Therapeutic whole body hyperthermia (WBH), with body temperatures raised up to 42.2°C, has been used in the treatment of advanced tumors and might act via changes to the immune system (Dieing et al. 2007). ...
Heat acclimation results in whole body-adaptations that increase heat tolerance, and might also result in changed immune responses. We hypothesized that, after heat acclimation, tumor necrosis factor alpha, interleukin 6 and the lymphocyte count would be altered. Heat acclimation was induced in 6 healthy men by 100 min of heat exposure for 9 days. Heat exposure consisted of (1) 10 min of immersion up to chest-level in water at 42°C and (2) 90 min of passive heating by a warm blanket to maintain tympanic temperature at 37.5°C. The climatic chamber was maintained at 40°C and a relative humidity of 50%. Blood samples were analyzed before and after heat acclimation for natural killer (NK) cell activity, counts of lymphocytes B and T, before and after heat acclimation for peripheral blood morphology, interleukin 6, tumor necrosis factor alpha, and cortisol. A Japanese version of the profile of mood states questionnaire was also administered before and after acclimation. The concentrations of white blood cells, lymphocytes B and T, cortisol, interleukin 6, tumor necrosis factor alpha and NK cell activity showed no significant differences between pre- and post-acclimation, but there was a significantly lower platelet count after acclimation and, with the profile of mood states questionnaire, there was a significant rise in anger after acclimation. It is concluded that heat acclimation by passive heating does not induce alterations in immune or endocrine responses.
The emergence of immunotherapies has revolutionized cancer treatment by leveraging the immune system to target malignancies, offering new hope where traditional therapies often fall short. Within this context, hyperthermia (HT) has re-emerged as a promising adjunctive treatment, capable of enhancing the effectiveness of radiotherapy, chemotherapy, and immunotherapy. HT influences both the innate and adaptive immune systems, enhancing the activity of immune cells such as neutrophils, NK cells, and dendritic cells, while also modulating the tumor microenvironment (TME) to promote immunogenic cell death (ICD) and reduce immunosuppressive conditions. These effects contribute to the transformation of immunologically “cold” tumors into “hot” tumors, making them more susceptible to immune-mediated destruction. Furthermore, HT can amplify the efficacy of immune checkpoint inhibitors (ICIs) by improving immune cell infiltration, inducing damage-associated molecular pattern (DAMP) release, and enhancing antigen presentation. Preclinical and clinical studies support the combination of HT with ICIs, demonstrating improved outcomes in otherwise resistant tumors. However, the full therapeutic potential of the different technologies allowing to apply HT remains to be fully understood, and further research is needed to optimize treatment protocols, explore the differential impacts of local versus whole-body hyperthermia, and identify biomarkers for patient stratification. This review underscores the multifaceted role of HT in immunity and its potential to significantly enhance the efficacy of immunotherapy.
Neurodegenerative diseases (NDs) and Long COVID represent critical and growing global health challenges, characterized by complex pathophysiological mechanisms including neuronal deterioration, protein misfolding, and persistent neuroinflammation. The emergence of innovative therapeutic approaches, such as whole-body hyperthermia (WBH), offers promising potential to modulate underlying pathophysiological mechanisms in NDs and related conditions like Long COVID. WBH, particularly in fever-range, enhances mitochondrial function, induces heat shock proteins (HSPs), and modulates neuroinflammation—benefits that pharmacological treatments often struggle to replicate. HSPs such as HSP70 and HSP90 play pivotal roles in protein folding, aggregation prevention, and cellular protection, directly targeting pathological processes seen in NDs like Alzheimer's, Parkinson's, and Huntington's disease. Preliminary findings also suggest WBH's potential to alleviate neurological symptoms in Long COVID, where persistent neuroinflammation and serotonin dysregulation are prominent. Despite the absence of robust clinical trials, the therapeutic implications of WBH extend to immune modulation and the restoration of disrupted physiological pathways. However, the dual nature of hyperthermia's effects—balancing pro-inflammatory and anti-inflammatory responses—emphasizes the need for dose-controlled applications and stringent patient monitoring to minimize risks in vulnerable populations. While WBH shows potential interest, significant challenges remain. These include individual variability in response, limited accessibility to advanced hyperthermia technologies, and the need for standardized clinical protocols. Future research must focus on targeted clinical trials, biomarker identification, and personalized treatment strategies to optimize WBH's efficacy in NDs and Long COVID. The integration of WBH into therapeutic paradigms could mark a transformative step in addressing these complex conditions.
As a contrast and heating agent, the admissibility of nanoferrites grows gradually. To prepare Co1-xZnxFe2O4, coprecipitation procedure was utilized. The nanoferrites were coated with chitosan. The configuration of spinel ferrite has been verified by XRD spectra and FTIR. Bright- and dark-field TEM and HRTEM were obtained to investigate the surface structure. From EDS analysis, the elemental composition has been determined. The shift of magnetic behavior has been elaborated by the Mössbauer analysis. The change in saturation magnetization and coercivity with zinc proportion has been studied in detail by the M–H curve. The hydrodynamic diameter and polydispersity index (PDI) of the chitosan-coated solution at concentrations 1 mg/ml and 2 mg/ml were measured. An in vitro cytotoxicity test on HeLa cancer cells was investigated. The effect of the contrast agent was investigated by TOF experiments. The heating profile of the samples was examined. It was observed that Co0.6Zn0.4Fe2O4 was suitable for hyperthermia applications.
Though it has long been thought that the immune system is implicated in the pathophysiology of heat stroke, the underlying mechanisms are still poorly understood. As it has been reported in the literature that lymphocyte disturbance occurs in heat stroke patients or animals, we attempted to seek experimental evidence to define the role of lymphocytes in the pathophysiology of heat stroke. In our study, we used male Balb/c mice to establish a passive heat stroke model. We found that lymphocyte-deficient Severe combined immunodeficient (SCID) mice exposed to heat stress exhibited exacerbated heat stroke severity, which could be indicated by increased rates of mortality and serum levels of inflammatory cytokines compared to wildtype control mice. We further showed, through the depletion of T lymphocytes in wildtype mice and the transfer of wildtype lymphocytes into SCID mice, respectively, that T lymphocytes were both necessary and sufficient to alleviate the severity of heat stroke by inhibiting the early inflammatory response. Moreover, we found that the severity of heat injuries in heat-stressed wildtype mice showed great inter-individual variability, and the early number of T lymphocytes could be negatively associated with the severity of heat stroke. Our results suggest that lack of T lymphocytes could exacerbate the severity of heat stroke by augmenting inflammatory response, and the early circulating T lymphocytes may serve as a potential biomarker for the diagnosis of heat stroke.
Nanoparticle induced hyperthermia has been considered as a promising approach for cancer treatment for decades. The local heating ability and drug delivery potential highlight a diversified possibility in clinical application, therefore a variety of nanoparticles that has been developed accordingly. However, currently, only a few of them have been translated into clinical stage indicating the ‘nanoparticle medically underserved’ situation, which encourages their comprehensive biomedical exploration. This study presents a thorough biological evaluation of previous well-developed dual pH- and thermo- responsive magnetic Doxorubicin-nanocarrier (MNC-DOX) in multiple cancer cell lines. The biocompatible of the nanocomposites has been proved by the MTT assay on primary cell lines. The histology and fluorescence microscopy imaging revealed the efficient but various cellular uptaking of nanocarriers among cell lines. The IC50 of MNC-DOX is significantly lower than free DOX without alternative magnetic field (AMF), which implied the potential to lower the systemic cytotoxicity in clinical research. The concurrent thermo-chemotherapy generated by this platform has been successfully achieved under alternating magnetic field (AMF). Promising effective synergistic results have been demonstrated through in vitro study in multi-model cancer cell lines via both trypan blue exclusion method and bioluminescence imaging method. Furthermore, the two most used magnetic hyperthermia modality, namely intracellular and extracellular treatments have been compared on the same nanocarriers in all 3 cell lines, which showed treatment after internalization is not required but preferable. These results lead to the conclusion that this dual responsive nanocarrier has extraordinary potential to serve as a novel broad-spectrum anticancer drug and worth to be pursued for potential clinical applications.
Multiple sclerosis (MS) is a prevalent neurological disease among adults worldwide (∼2.5 million cases). Disease modifying therapies are only modestly effective for slowing long-term progression of pathological and disability outcomes, underscoring the importance of considering other approaches for managing MS. One approach to treating MS is to reduce the load of lymphocytes that could enter the central nervous system (CNS). Most pharmaceuticals work by downgrading the immune system, but have numerous adverse side effects. We hypothesize that using focused ultrasound (FUS) to heat the cervical lymph nodes, which house the lymphocytes that primarily service the CNS, will reduce the lymphocyte load and alleviate MS with minimal side effects. In our pilot study, FUS was used to produce hyperthermia in cervical lymph nodes of rats having experimental autoimmune encephalomyelitis (EAE), the animal model of MS, in order to alleviate severity of EAE. EAE was induced in rats through injection of myelin oligodendrocyte glycoprotein (MOG (1–125)) and EAE disability scores, on a scale of 0 to 5, were recorded over 21 days post injection. At the onset of EAE symptoms, one set of rats was treated with FUS while another set of rats was sham treated. Specifically, rats were treated at day 9 and day 12 post MOG injection. During therapy, a focused ultrasound transducer (f/3) operating at 0.5 MHz was positioned over the jaw of a rat with the focus of the transducer placed above the skin surface to heat the superficial cervical lymph nodes just under the skin surface. A temperature of 43–44 °C was induced via FUS in the lymph nodes of the rats for 20 minutes on both the right and left side of the jaw. A thermocouple was used to record the temperature near the lymph nodes during exposures. An EAE remittance score was tallied for all rats, defined as the reduction in the EAE score achieved after the maximum EAE score was reached. On average the EAE remittance score for FUS treated rats was 1.14 ± 0.48 versus 0.33 ± 0.27 for sham treated rats. These differences were statistically significant (p = 0.037). Remittance of the EAE disability scores were highly correlated with the last therapy application. Therefore, FUS treatment of cervical lymph nodes in rats with EAE resulted in a significant reduction in EAE score, which was not observed in sham treated rats. This pilot study is the first ever FUS treatment of EAE in a rat model.
All over the world many people consume food and drink too hot. The caution initially exercised by parents when feeding infants tends to be neglected as children grow older. As children gradually become accustomed to consuming food and drink as hot as their parents do, most experience a dramatic reduction in the sensitivity of their oral mucosa to pain and thus also in their "natural" resistance to hot nutrition. Soups at a temperature of +70 °C are regarded by most grown-ups as "pleasantly warm", Food and drink thermometers are hardly ever used for monitoring purposes. The repeated exposure to heat caused by the consumption of hot food and drink has numerous consequences for our health. The mucosa of the upper digestive tract are damaged and made more susceptible to microbial infections. Inflammations spread in the alimentary canal and attack the respiratory tract and adjacent organ systems. The immune system suffers. The regular consumption of hot food and drink appear to create favourable conditions for allergies, neurodermatitis and asthma and may even cause these diseases. Evidence also exists suggesting the possibility of a connection with autoimmune illnesses such as multiple sclerosis, diabetes mellitus type 1 and arteriosclerosis. in many industrial countries public service institutions are for reasons of hygiene obliged by law to observe minimum temperatures between +60 °C and +75 °C when serving warm or hot food. For health reasons, however, it must be recommended that food or drink should not be consumed hotter than body temperature, namely +37 °C. Food business operators should regard "high consumption temperature" as a potential hazard when Implementing an HACCP. system. We show how this hazard can be eliminated without loss of control over microbiological hazards. We suggest and justify +43 °C as a critical limit for the maximum temperature of consumption. Check-ups have proved the value of the recommendation to avoid hot food and drink. An improvement in the present situation will necessitate not only fundamental changes in the consciousness both of consumers and of those with public responsibility but also greater interest in the worlds of food science and medicine. If these conditions are fulfilled, our countries may expect significant economic benefits.
Radiotherapy represents an essential treatment option for the majority of cancer patients in different stages of their disease. Physical achievements of the recent years led to the implementation of high precision treatment planning procedures, and image-guided dose delivery is current state of the art. Yet, radiotherapy still faces several limitations with cancer intrinsic radioresistance being a key driver of therapeutic failure. Accordingly, the mechanisms orchestrating radioresistance and their therapeutic targeting by combined modality approaches are in the center of attention of numerous radiation oncologists. In the present review, we summarize and discuss therapeutic approaches that exploit the heat shock response, either by hyperthermia or by pharmacological heat shock protein inhibition, in combination with radiotherapy. These strategies appear particularly promising, since they sensitize cancer cells to irradiation-induced cell death and at the same time have proven the potential to promote systemic anti-tumor immune mechanisms, which may target not only locally surviving tumor cells, but also distant out-of-field metastases.
Copyright © 2015. Published by Elsevier Ireland Ltd.
Abstract Cytokines are intracellular peptides that serve as immune mediators. The levels of both pro- and anti-inflammatory cytokines have been demonstrated to rise in the event of heat stroke in both human and animal models. Different hyperthermic states, including both normal exercise-induced hyperthermia and classical and exertional heat stroke, result in unique characteristic profiles of plasma cytokines. The complexity of the interaction between pro- and anti-inflammatory cytokines is outlined in the vast number of experimental studies and clinical observations reported in the literature. However, there is no unanimous logic in studying the changes in cytokine levels, and therefore, it is difficult to compare the effects seen in the different reports. The strong inflammatory response to heat stroke increases after the cessation of heat stress and is intricately involved both in damage-generating processes and in repair mechanisms that are put into action during the recovery phase. In surviving individuals, this response diminishes in magnitude as time progresses and eventually subsides to allow return-to-normal homeostasis. A greater magnitude of the inflammatory response is often associated with poor prognosis and even fatalities, suggesting an imbalance of the immune system, which causes an unregulated inflammatory response. This review describes the common known processes relating to the predominant cytokines altered in the event of heat injury. The role of cytokines, specifically in the pathophysiology of heat stroke, is elaborated and depicted as part of a biaxial model pertaining to the physiological and cellular/biochemical aspects of heat stroke.
Objective
The aim of our study was to assess the efficacy of regional hyperthermia combined with intrapleural chemotherapy and to evaluate the effect on the immunologic cells and vascular endothelial growth factor (VEGF) in patients with malignant pleural effusion.
Methods
The 102 patients with malignant pleural effusion were included in this study: 52 patients undergoing regional hyperthermia with intrapleural chemotherapy (HICT), and 50 patients treated with intrapleural chemotherapy (ICT). Chemotherapy was administered into the thoracic cavity weekly through a tube with CDDP (dose = 40 mg/m2), and hyperthermia was performed twice a week for 60 minutes following the ICT. We evaluated the response rates and side-effects after 4 weeks. Before and after the treatment, T cell subsets and NK cells were detected by flow cytometry and VEGF was measured with ELISA kits.
Results
Compared HICT to ICT, the overall response rates of the whole group, breast cancers and lung cancers were 80.8% vs 54% (P < 0.01), 86.7% vs 56.3% (P > 0.05) and 78.4% vs 52.9% (P < 0.05) respectively. The ratios of CD4+, CD4+/CD8+ and NK cells increased and the concentration of VEGF decreased more significantly after HICT.
Conclusion
We concluded that combined regional hyperthermia with intrapleural chemotherapy could control the malignant pleural effusion effectively with mild toxicity. The levels of the T cell subset, NK cells and VEGF in both blood and effusion changed obviously.
The aim of this study was to determine the effects of whole body heat in combination with exercise on the oxidative stress and acute phase immune response. Nine male endurance-trained athletes voluntarily performed two running bouts of 45 minutes at 75-80% of VO(2max) in a climatic chamber in two conditions: cold and hot humid environment. Leukocyte, neutrophil and basophil counts significantly rose after exercise in both environments; it was significantly greater in the hot environment. Lymphocyte and neutrophil antioxidant enzyme activities and carbonyl index significantly increased or decreased after exercise only in the hot environment, respectively. The lymphocytes expression of catalase, Hsp72 and CuZn-superoxide dismutase was increased in the hot environment and Sirt3 in the cold environment, mainly during recovery. In conclusion, the increased core body temperature results in the acute phase immune response associated to intense exercise and in the immune cell adaptations to counteract the oxidative stress situation.
Dans ce travail, nous passons en revue les efforts de formulation et de préformulation pharmaceutiques pertinentes pour les nouvelles modalités d'hyperthermie magnétiquement induite dans le traitement des lésions cancéreuses pour lesquelles une thermothérapie est indiquée, ou pour des indications de novo dans certaines situations cliniques. Nous introduirons d'abord les principes biologiques généraux sous-jacents à l'utilisation de l'hyperthermie, compte tenu des moyens techniques pour générer l'hyperthermie actuellement accessibles, nous détaillerons plus précisément différentes modalités magnétiques de chauffage. Nous présenterons alors une synthèse des formulations décrites dans la littérature, en comparant leurs spécificités, avantages et inconvénients. Premièrement, nous considérerons les biomatériaux basés sur les céramiques, les verres et les ciments, pour hyperthermie à médiation magnétique dans le traitement des tumeurs solides de l'os, tenant compte de ses spécificités biologiques. Dans un deuxième temps seront considérées les formulations destinées à l'induction magnétique d'une hyperthermie localisée pour le traitement de tumeurs solides des tissus mous, en insistant sur les modulations biochimiques et pharmacologiques. Dans la dernière partie, nous considérerons les formulations de liposomes magnétiques qui peuvent être également administrées dans divers types de tumeurs. Nous n'avons pas détaillé ici les formulations magnétiques pour l'hyperthermie magnétique fluide qui sont basées sur l'administration de suspensions de nanoparticules magnétiques stabilisées par un revêtement de surface permettant des applications biologiques. Les importantes considérations biologiques et immunologiques qui sont associés à ces formulations seront décrites. En tout point, cette revue se concentrera sur l'importance de la formulation pharmaceutique et sur les interactions extrêmement complexes en lien avec l' hyperthermie qui devraient être pris en compte dans diverses applications médicales.
Nosocomial hyperthermia (fever) occurs in about 30% of all medical patients at some time during their hospital stay. In patients admitted to the intensive care unit with severe sepsis the incidence of hyperthermia is greater than 90%, while in a specialized neurological critical care unit the incidence is reported as 47%. In contrast, hyperthermia during anaesthesia is rare owing to the impairment of thermoregulation by anaesthetic agents. This article is designed to give an overview on the various causes of hyperthermia with special emphasis on fever during general and regional anaesthesia in general and neurological critical care patients.
We examined the specificity of the recently reported alterations in circulating lymphocytes in heatstroke by determining lymphocyte subsets in 14 consecutive heatstroke patients before and after cooling and in 7 heat-stressed controls using single- or two-color immunofluorescence flow cytometry. The relationship with catecholamine levels was also studied. In heatstroke, percentages of T (CD3(+)/CD19(-)), T-helper (CD4(+)/CD8(-)), T-inactive [CD3(+)/human leukocyte antigen-DR-], CD11a+, CD11c+, and CD44(+) lymphocytes were significantly decreased, whereas percentages of T-suppressor-cytotoxic (CD8(+)/CD4(-)), natural killer (NK; CD3(-)/CD16(+) or CD56(+)), CD3(+)/CD16(+) or CD56(+), and CD54(+) lymphocytes were significantly increased, compared with 11 normal controls. The changes in the absolute numbers of lymphocyte subsets were in the same direction and were significant for T-helper, T-suppressor-cytotoxic, NK, CD3(+)/CD16(+) or CD56(+), and CD11c+ lymphocytes. Milder but significant changes in percentages of T-helper, T-suppressor-cytotoxic, CD11c+, and CD44(+) lymphocytes were seen in heat stress. Cooling was associated with partial or complete normalization, further derangement (CD11a+, CD11c+), or overcorrection (NK, T-suppressor-cytotoxic, CD11b+) of abnormal percentages of lymphocyte subsets. Norepinephrine levels were significantly elevated in heatstroke (4.7-fold) and heat stress (3.2-fold), but did not significantly correlate with lymphocyte subsets. We conclude that heatstroke is associated with significant changes in percentages and in absolute numbers of a wide range of circulating lymphocyte subsets that are not related to elevated catecholamine levels or totally normalized by cooling. Similar, albeit milder, changes are seen in heat stress, suggesting that the two syndromes represent a continuum.
Induction of hyperthermia (39 degrees C) in human volunteers by immersion in warm water (41-45 degrees C) rapidly alters the cell populations in the peripheral blood. In addition to granulocytosis, there is an alteration of the normal ratios among T-lymphocyte subsets. Following in vitro mitogen stimulation, lymphocytes from hyperthermic individuals produce as much as 10-fold more interferon-gamma (IFN-gamma) than cells withdrawn at basal core temperatures from the same individuals. A temperature threshold of 39 degrees C for this response suggests potential relevance to fever. No change was noted in the activity of the macrophage population. The possible involvement of interleukin-2 (IL-2) in this enhanced production is discussed. No changes were noted in the circulating levels of IFN-gamma.
Propriocidal regulation of T cells refers to apoptosis induced by interleukin 2 (IL-2) activation with subsequent antigen receptor stimulation. We examined whether natural killer (NK) cells exhibited cytokine- and ligand-induced death similar to activated T cells. Peripheral NK cells were examined for ligand-induced death using antibodies to surface moieties (CD2, CD3, CD8, CD16, CD56), with and without prior activation of IL-2. Only those NK cells stimulated first with IL-2 and then with CD16 exhibited ligand-induced death; none of the other antibody stimuli induced this phenomenon. Next we examined various cytokines (IL-2, IL-4, IL-6, IL-7, IL-12, IL-13, interferon alpha and gamma) that can activate NK cells and determined if CD16-induced killing occurred. Only IL-2 and IL-12 induced NK cell death after occupancy of this receptor by aggregated immunoglobulin or by cross-linking with antireceptor antibody. The CD16-induced death was inhibited by herbimycin A, indicating that cell death was dependent upon protein tyrosine kinases. Identical to T cells, the form of cell death for NK cells was demonstrated to be receptor-induced apoptosis. Overall these data indicate that highly activated NK cells mediate ligand-induced apoptosis via signaling molecules like CD16. Whereas the propriocidal regulation of T cells is antigen specific, this is not the case for NK cells due to the nature of the receptor. The clinical implications of this finding are considered.
Apoptosis in tumor and normal tissues was examined in rats treated with whole-body hyperthermia (WBH; 41.5 degrees C for 2 h). WBH alone produced 0.5 day of tumor growth delay (TGD) in a fibrosarcoma and 5.8 days of TGD in the Ward colon carcinoma. This difference in WBH-induced TGD indicates that the fibrosarcoma is relatively resistant to WBH, whereas the Ward colon carcinoma is relatively heat sensitive. A quantitative histological assay for apoptosis demonstrated that the extent of apoptosis in the fibrosarcoma reached a maximum level of 19% 4 h after WBH and returned to the control level by 24 h. In contrast, WBH induced apoptosis with a peak value of 43% at 8 h in the Ward colon carcinoma, and the apoptotic level remained elevated above the control level until 48 h after WBH. Within normal tissues, the spleen and the lymph nodes showed WBH-induced apoptosis; however, the highest level of WBH-induced apoptosis as well as the most prolonged increase in apoptotic levels occurred in the thymus. The WBH-induced apoptosis in the thymus remained elevated above the control level until 48 h after WBH. Within the entire gastrointestinal tract, the small intestine was the most sensitive to WBH. Apoptotic cells were observed in the small bowel mucosa following WBH exposure. We also noted a minor WBH-induced increase in the apoptotic level in the bone marrow. Except for the case of the thymus, increased apoptotic levels in the normal tissues declined after peak levels at 4 h, and apoptosis above control levels was not seen beyond 12 h following WBH. Thus, within the normal tissues, WBH-induced apoptosis declined to basal levels within 12-48 h. These data indicate that both the extent and the kinetics of WBH-induced apoptosis differ between the two tumors and, meaningfully, between tumor and normal tissues. The extent and duration of apoptosis seem to correlate with tumor response to WBH.
Increases in catecholamines have been shown to induce changes in migration of lymphocytes, in particular NK cells. To analyze the mechanisms of catecholamine-induced NK cell trafficking, normal healthy male human subjects and splenectomized individuals were infused with either adrenaline (0.10 microgram/kg/min), noradrenaline (0.15 microgram/kg/min), or NaCl i.v. for 20 min. Lymphocyte subsets (CD3+, CD4+, CD8+) transiently increased after administration of both catecholamines, with most pronounced increases (up to 600%) in NK cell numbers (CD16+ or CD56+) after infusion of adrenaline. These changes in NK cell numbers and function were accompanied neither by alterations in expression of adhesion molecules (CD11a), CD11b, CD31, CD43, CD44, CD62L) on NK cells nor by changes in plasma concentrations of soluble (s) adhesion molecules (sVCAM-1, sICAM-1, sE-selectin). Comparable increases in lymphocyte subsets were observed in splenectomized subjects, suggesting lymphocyte recruitment from other sources than the spleen. Furthermore, catecholamine-induced increases in lymphocyte subsets could be inhibited by pretreatment with the nonselective beta-adrenoceptor antagonist propranolol, but not by the beta1-selective antagonist bisoprolol. These data demonstrate that adrenaline and noradrenaline modulate the migratory capacity of human NK cells via spleen-independent beta 2-adrenoceptor mechanism.
The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with 'sympathetic storm' due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a beta-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the beta-receptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.
The effect of mild hyperthermia on a cultured rat malignant fibrous histiocytoma (MFH) cell line, MFH‐2NR, was investigated. MFH cells in log‐phase (growing phase) were heated at 41°–44°C for 1 hr. Hyperthermic treatment at 41°C did not substantially affect cell proliferation and treatment at 44°C caused necrosis. After hyperthermic treatment at 42° or 43°C, proliferation of MFH cells was arrested and morphological changes characteristic of apoptosis, cell shrinkage accompanying apoptotic bodies and chromatin condensation, became apparent. Hyperthermia‐induced apoptosis was further confirmed by terminal deoxynucleotidyl transferase staining and a ladder pattern on agarose gel electrophoresis. Flow cytometric analysis indicated that the population in the G1 phase of the cell cycle significantly decreased with a concomitant increase in apoptotic cells, indicating that apoptosis might occur mainly in the G1 phase population. © 1996 Wiley‐Liss, Inc.
A single treatment of low‐temperature, long‐duration, whole‐body hyperthermia of either severe combined immunodeficient (SCID) mice bearing human breast tumor xenografts or Balb/c mice bearing syngeneic tumors for 6–8 hr can cause a temporary reduction of tumor volume and/or a growth delay. In both animal model systems, this inhibition is correlated with the appearance of large numbers of apoptotic tumor cells. Because this type of mild heat exposure, comparable to a common fever, is not itself directly cytotoxic, other explanations for the observed tumor cell death were considered. Our data support the hypothesis that this hyperthermia protocol stimulates some component(s) of the immune response, which results in increased antitumor activity. In support of this hypothesis, increased numbers of lymphocyte‐like cells, macrophages, and granulocytes are observed in the tumor vasculature and in the tumor stroma immediately following this mild hyperthermia exposure. In Balb/c mice, an infiltrate persists in the tumor for at least 2 weeks. Using the SCID mouse/human tumor system, we found that both host natural killer (NK) cells and injected human NK cells were increased at the site of tumor following hyperthermia treatment. Experiments using anti‐asialo‐GM1 antibodies indicate that the tumor cell apoptosis seen in the SCID mouse appears to be due largely to the activity of NK cells, although additional roles for other immunoeffector cells and cytokines appear likely in the immunologically complete Balb/c model. Another interrelated hypothesis is that immunoeffector cells may have greater access to the interior of the tumor because we have observed that this treatment causes an obvious expansion in the diameter of blood vessels within the tumor and an increase in nucleated blood cells within the vessels, which persists as long as 2 weeks after treatment. Further study of the mechanisms by which mild hyperthermia exerts antitumor activity could result in this treatment protocol being used as an effective, nontoxic adjuvant to immunotherapy and/or other cancer therapies. J. Cell. Physiol. 177:137–147, 1998. © 1998 Wiley‐Liss, Inc.
Fever is associated with increased survival during acute infection, although its mechanism of action is largely unknown. This study found evidence of an unexpectedly integrated mechanism by which fever-range temperatures stimulate lymphocyte homing to secondary lymphoid tissues by increasing L-selectin and α4β7 integrin–dependent adhesive interactions between circulating lymphocytes and specialized high endothelial venules (HEV). Exposure of splenic lymphocytes in vivo to fever-like whole-body hyperthermia (WBH; 39.8 ± 0.2°C for 6 hours) stimulated both L-selectin and α4β7 integrin–dependent adhesion of lymphocytes to HEV under shear conditions in lymph nodes and Peyer patches. The adhesiveness of HEV ligands for L-selectin and α4β7 integrin (ie, peripheral lymph node addressin and mucosal addressin cell adhesion molecule-1) also increased during WBH or febrile responses associated with lipopolysaccharide-induced or turpentine-induced inflammation. Similar increases in HEV adhesion occurred during hyperthermia treatment of lymph node and Peyer patch organ cultures in vitro, indicating that the local lymphoid tissue microenvironment is sufficient for the hyperthermia response. In contrast, WBH did not augment adhesion in squamous endothelium of nonlymphoid tissues. Analysis of homing of α4β7hi L-selectinlo murine TK1 cells and L-selectinhi α4β7 integrin-negative 300.19/L-selectin transfectant cells showed that fever-range temperatures caused a 3- to 4-fold increase in L-selectin and α4β7 integrin–dependent trafficking to secondary lymphoid tissues. Thus, enhanced lymphocyte delivery to HEV by febrile temperatures through bimodal regulation of lymphocyte and endothelial adhesion provides a novel mechanism to promote immune surveillance.
This chapter elucidates the role of endogenous opioid agonists in hyperthermic disorders. Opiates are drugs known for a long time due to their analgesic, euphoric, antidiarrheal, cough-suppressing, and addictive effects. Without doubt, some other effects of opiates have also been known to the user and abuser of these substances for several centuries. There are some findings suggesting that opioids may be involved in the mechanisms of both fever and heat stroke. It is generally appreciated that the interactions between the opioidergic system and thermoregulation are complex and that a thermoregulatory effect of a particular opioid substance often depends on a large number of factors, including the route of administration, dose of the drug, the degree of stress, and the ambient temperature. When evaluating thermoregulatory effects of exogenous opioid antagonists, one finds that these drugs do not significantly influence Tb under normal conditions. The apparent involvement of opioids in pathological rather than physiological responses contributes to the keen interest of physicians in opiate antagonists, particularly naloxone. Potent therapeutic effects of this drug, including a drastic reduction in mortality, have been observed in several experimental models of hyperthermic disorders.
Objective: To examine the relationship between circulating interleukin-10 (IL-10) and the occurrence of lymphocyte apoptosis after surgical/anesthesia trauma. Methods: Data were collected prospectively on 18 adult patients undergoing elective major surgery. Blood sampling for assessment of lymphocyte apoptosis and IL-10 levels was performed on the day before surgery (t(0)) and at 24 and 96 hours after operation (t(1) and t(2), respectively). After lymphocyte isolation, quantification of apoptosis was made by staining apoptotic cells with 7-amino-actinonmycin D, Plasma IL-10 concentrations were measured using enzyme-linked immunosorbent assay, Results: A significantly increased frequency of apoptotic CD4(+) and CD8(+) cells (p < 0.05) was observed at t(1) measurement (8,10% +/- 0.58% and 12.21% +/- 1.47% for CD4(+) and CD8+, respectively) compared with preoperative values (1.53% +/- 0.38% and 1.32% +/- 0.45% for CD4(+) and CD8(+), respectively). Plasma IL-10 levels showed a significant elevation at both t(1) and t(2) times, peaking at t(1). At t(1), IL-10 levels were correlated with the frequency of CD4(+) and CD8(+) apoptotic lymphocytes (r = 0.78, p = 0.0005 for IL-10 vs. apoptotic CD4(+); r = 0.71, p = 0.003 for IL-10 vs. apoptotic CD8(+)), Conclusion: surgical trauma is associated with a significant but transient increase in lymphocyte commitment to apoptosis and IL-10 production. The exact relationship linking the overproduction of IL-10 with lymphocyte apoptosis after a surgical operation is still elusive and requires further investigation.
BACKGROUND
Natural cytotoxicity, mediated by natural killer (NK) cells and cells with lymphokine-activated killer (LAK) activity, is believed to play an important role in host anti-cancer defense mechanisms.METHODS
The authors critically review recent publications on the role of natural cytotoxicity in patients with cancer.RESULTSIn patients with cancer, several studies have noted variations in the numbers and activity of NK and cells with LAK activity in different body compartments. NK cell activity in the peripheral blood lymphocytes (PBLs) is higher than that found in lymph nodes and within tumors, and this appears to be due to the presence of suppressor factors. The natural cytotoxicity of PBLs in patients with different types of cancers varies. However, there appears to be a trend for natural cytotoxicity to be reduced in certain cancer patients, possibly related to tumor volume or dissemination. Anti-cancer treatments (e.g., surgery, hormonal modulation, radiotherapy and chemotherapy) can also result in suppression of natural cytotoxicity, although the long-term effect on response to treatment and development of metastases is at present unknown.CONCLUSIONSNK and LAK cells, through the use of immune biologic modifiers, have been demonstrated to have a therapeutic role in the treatment of human cancers. Further studies are required to determine the optimal dosages and combinations of chemotherapeutic agents, the timing of surgery, and the adjuvant use of immune biologic response modifiers. An increasing awareness and understanding of this field, may allow for the future development of anti-cancer therapies. Cancer 1996;77:1226-43.
Natural killer (NK) cell circulation is subject to adrenergic regulation. Exactly how NK cells are released into the circulation is unknown. In an attempt to identify some of the mechanisms, the present report focuses on aspects of adhesion regulation of NK cells. Results demonstrate that interactions between NK and endothelial cells (EC)in vitrocan be reduced by β2-adrenoceptor stimulation for as long as the receptor stimulation occurs. The level of soluble adhesion molecules (sICAM-1, sE-selectin, sVCAM-1)in vivoremained unchanged during adrenaline infusion.In vitroanalyses further reveal the requirement for Ca2+/Mg2+in NK–EC adhesion. Blocking studies indicate the involvement of several members of the β1(CD29)- and β2(CD18)-integrin family, reducing NK cell adhesion by 28 to 39%. Stimulation of β2-adrenoceptors in the presence of these blocking antibodies further reduced NK adhesion by an average of 22%. Analysis of NK cell adhesion to various extracellular matrix components demonstrates significant NK cell adhesion to fibronectin but much less to laminin or collagens I and IV. NK cell adhesion to fibronectin was reduced by 50% upon β2-adrenoceptor stimulation, independent of the VLA-4/VLA-5 binding site on fibronectin. Together these results contribute to understanding the influences of β-adrenoceptor stimulation on NK cell circulation and adhesion.
The effect of mild hyperthermia on a cultured rat malignant fibrous histiocytoma (MFH) cell line, MFH-2NR, was investigated. MFH cells in log-phase (growing phase) were heated at 41°–44°C for 1 hr. Hyperthermic treatment at 41°C did not substantially affect cell proliferation and treatment at 44°C caused necrosis. After hyperthermic treatment at 42° or 43°C, proliferation of MFH cells was arrested and morphological changes characteristic of apoptosis, cell shrinkage accompanying apoptotic bodies and chromatin condensation, became apparent. Hyperthermia-induced apoptosis was further confirmed by terminal deoxynucleotidyl transferase staining and a ladder pattern on agarose gel electrophoresis. Flow cytometric analysis indicated that the population in the G1 phase of the cell cycle significantly decreased with a concomitant increase in apoptotic cells, indicating that apoptosis might occur mainly in the G1 phase population. © 1996 Wiley-Liss, Inc.
The potential for 41.8 dgC whole body hyperthermia (WBH) to enhance ionizing irradiation and cytotoxic chemotherapy without a commensurate increase in normal tissue toxicity is currently receiving renewed clinical interest. Additionally, WBH may have other biological sequela which may be clinically exploited. In this paper, data are summarized revealing the ability of WBH to induce elevated plasma levels of granulocyte-colony stimulating factor (G-CSF), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) within hours of WBH. Data regarding TNF-α shows induction in only a proportion of patients. No induction of C-reactive protein (CRP) or the following cytokines was observed: granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-11 (IL-11), interleukin-12 (IL-12), macrophage-colony stimulating factor (M-CSF), and macrophage inflammatory protein-1α (MIP-1α). Data regarding interleukin-3 (IL-3) and transforming growth factor-β1 (TGF-β1) were variable and inconclusive. The implications of these results to past and future clinical trials are discussed.
Lymphocyte migration is an essential process for immune surveillance and for promoting cell-cell interactions necessary to generate an immune response. This report examined whether catecholamine prestimulation would alter the pattern of lymphocyte homing to spleen and lymph nodes in mice as determined by tracking fluorescently labeled cells. The results of cell sorter analysis showed that catecholamine-pretreated cells had increased accumulation in spleen and lymph nodes 1 and 2 h after i.v. injection. In addition, microscopic analysis showed that labeled cells migrated from the splenic red pulp to T-cell regions of the white pulp over a 2-h time course. Within the lymph nodes, labeled cells localized predominantly to the pericortex. Additional studies examined the migration of lymphocytes to lymphoid tissues of NGF-transgenic mice that have sympathetic hyperinnervation of spleen and peripheral lymph nodes. In contrast to the studies above, migration of T-cells from control mice to lymphoid tissues of the hyperinnervated mice was not different than that in control mice in most tissues. The accumulation of lymphocytes in lymphoid tissues is a balance between the influx of newly migrated cells and efflux back into the circulation. The studies in this report lend support to other studies showing catecholamine modulation of lymphocyte migration and homing, but it is a complex process about which much has yet to be understood.
Significantly less natural killer (NK) activity is exhibited by human lymphocytes when the NK assay is carried out at temperatures above 37°C. Hyperthermia seems to act directly on the NK effector cells. The effect is partially abrogated by treatment of the heated cells with human leucocyte interferon.
There are great differences in heat sensitivity between different cell types and tissues. However, for an isoeffect induced in a specific cell type or tissue by heating for different durations at different temperatures varying from 43-44 degrees C up to about 57 degrees C, the duration of heating must be increased by a factor of about 2 (R value) when the temperature is decreased by 1 degrees C. This same time-temperature relationship has been observed for heat inactivation of proteins, and changing only one amino acid out of 253 can shift the temperature for a given amount of protein denaturation from 46 degrees C to either 43 or 49 degrees C. For cytotoxic temperatures <43-44 degrees C, R for mammalian cells and tissues is about 4-6. Many factors change the absolute heat sensitivity of mammalian cells by about 1 degrees C, but these factors have little effect on Rs, although the transition in R at 43-44 degrees C may be eliminated or shifted by about 1 degrees C. R for heat radiosensitization are similar to those above for heat cytotoxicity, but Rs for heat chemosensitization are much smaller (usually about 1.1-1.2). In practically all of the clinical trials that have been conducted, heat and radiation have been separated by 30-60 min, for which the primary effect should be heat cytotoxicity and not heat radiosensitization. Data are presented showing the clinical application of the thermal isoeffect dose (TID) concept in which different heating protocols for different times at different temperatures are converted into equivalent minutes (equiv) min at 43 degrees C (EM(43)). For several heat treatments in the clinic, the TIDs for each treatment can be added to give a cumulative equiv min at 43 degrees C, namely, CEM(43). This TID concept was applied by Oleson et al. in a retrospective analysis of clinical data, with the intent of using this approach prospectively to guide future clinical studies. Considerations of laboratory data and the large variations in temperature distributions observed in human tumors indicate that thermal tolerance, which has been observed for mammalian cells for both heat killing and heat radiosensitization, probably is not very important in the clinic. However, if thermal tolerance did occur in the clinical trials in which fractionation schemes were varied, it probably would not have been detected because with only the two-three-fold change in treatment time that occurs when comparing one versus two fractions per week, or three versus six total fractions, little difference would be expected in the response of the tumors since both thermal doses were extremely low on the dose-response curve. Data are shown which indicate that in order to test for thermal tolerance in the clinic and to have a successful phase III trial, the thermal dose should be increased about five-fold compared with what has been achieved in previous clinical trials. This increase in thermal dose could be achieved by increasing the temperature about 1.5 degrees C (from 39.5 to 41.0 degrees C in 90% of the tumor) or by increasing the total treatment time about five-fold. The estimate is that 90% of the tumor should receive a cumulative thermal dose (CEM(43)) of at least 25; this is abbreviated as a CEM(43) T(90) of 25. This value of 25 compares with 5 observed by Oleson et al. in their soft tissue sarcoma study. Arguments also are presented that thermal doses much higher than the CEM(43) T(90) induce the hyperthermic damage that causes the tumors to respond, and that the minimum CEM(43) T(90) of 25 only predicts which tumors that receive a certain minimal thermal dose in <90% of the regions of the tumors will respond. For example, in addition to a minimal CEM(43) T(90) of 25 a minimum CEM(43) T(50) of about 400 also may be required for a response. Finally, continuous heating for approximately 2 days at about 41 degrees C during either interstitial low dose-rate irradiation or fractionated high dose-rate irradiation, which we estimate could give a CEM(43) of 75, should be considered in order to enhance heat radiosensitization of the tumor as well as heat cytotoxicity. In order to exploit the use of hyperthermia in the clinic, we need a better understanding of the biology and physiology of heat effects in tumors and various normal tissues. As an example of an approach for mechanistic studies, one specific study is described which demonstrates that damage to the centrosome of CHO cells heated during G(1) causes irregular divisions that result in multinucleated cells that do not continue dividing to form colonies. This may or may not be relevant for heat damage in vivo. However, since normal tissues vary in thermal sensitivity by a factor of 10, similar approaches are needed to describe the fundamental lethal events that occur in the cells comprising the different tissues.
Cells with natural killer activity (NK) may play an important role in host defence against tumour cells. The lytic function of NK cells is very sensitive to hyperthermic inactivation. However, cells with NK activity isolated from rat spleen and exposed to 41-42.5 degrees C for 30 min could partially recover their cytotoxic activity after incubation at 37 degrees C. The recovered cytotoxicity was still NK-specific, as it only resulted in the lysis of YAC-1 sensitive targets, and could not lyse NK-resistant P815 mastocytoma cells. Conjugate formation assay using NK cells labelled with specific monoclonal antibody (mAb) 3.2.3 indicated that the binding of NK cells to targets was not significantly affected by heat treatment. Compared to controls, however, microtubule organizing centre (MTOC) reorientation towards the region of intercellular contact was reduced by 40% in heated effector cells. This was accompanied by a greater inhibition (62-77%) of NK lytic activity. Kinetic analysis indicated that MTOC reorientation capacity recovered following incubation at 37 degrees C. MTOC recovery was maximal 4 h after treatment whereas that of lytic activity peaked at 6 h. These data indicate that NK cells recover NK-specific lytic activity after heat inactivation. Moreover, our study demonstrates that hyperthermia interferes with post-binding MTOC reorientation, and further supports a role for microtubule in secretory processes involved in NK-mediated cytolysis.
This work was designed to test the hypothesis that elevations in body temperature of humans induce immunostimulation. Eight healthy volunteers were immersed in a water bath (water temperature 39.5 degrees C) for 2 h, during which their rectal temperature rose to 39.5 degrees C. On a later day they served as their own controls, being immersed into thermoneutral water (34.5 degrees C) for 2 h. Blood samples were collected before immersion, at body temperatures of 38 degree C, 39 degree C and 39.5 degree C, and 2 h after water immersion. The interleukin-2 (IL-2) enhanced natural killer (NK) cell activity (lysis per fixed number of mononuclear cells), as well as the proportion and total number of NK cells (CD16+ cells), increased significantly during hyperthermia compared with control values. The lymphocyte proliferative responses did not differ significantly between hyperthermia and thermoneutral conditions. The proportion of pan-T (CD3+) cells was maximally depressed 2 h after water immersion. The decreased proportion of CD3+ cells was mainly due to a decreased percentage of CD4+ cells (not significant). The proportion of B cells (CD19+ cells) did not fluctuate significantly, while a marked and significant increase in monocyte proportion (CD14+ cells) was found 2 h after hyperthermia. Two hours after hot water immersion the lymphocyte concentration declined while the neutrophil and monocyte concentrations were augmented. Induced hyperthermia causes significantly increased serum cortisol, plasma norepinephrine and plasma epinephrine concentrations compared to controls. It is possible that the altered immune functions induced by elevated body temperature can be ascribed to altered composition and function of blood mononuclear cells induced by elevated levels of stress hormones.
Febrile reactions often occur in cancer patients given various biological response modifiers such as alpha- or gamma-interferon or interleukin-2. The present studies were undertaken to determine the effects of moderately elevated temperatures (39 degrees C) on various immunological functions related to host defense against malignant cells. The production of the cytokines interleukin-1, interleukin-2, erythroid burst-promoting activity, and granulocyte-macrophage colony-stimulating factor from activated human mononuclear cells was assessed in vitro at 34, 37, and 39 degrees C and found to be reduced at 39 degrees C. The natural killer activity of human mononuclear cells preincubated for 18 h at various temperatures was also significantly reduced (P less than 0.001) at 39 degrees C. Although the addition of recombinant interleukin-1-beta, interleukin-2, and alpha-interferon during the 18-h incubation augmented natural killer activity at all temperatures, the enhancing effects were least apparent at 39 degrees C. Indomethacin increased cytokine-primed natural killer cell activity at all temperatures but did not reverse the inhibitory effects of elevated temperatures. These results suggest that the fever associated with treatment with pyrogenic cytokines may partially offset the direct stimulatory effects of these substances on cellular immune function.
Plateau-phase Chinese hamster ovary cells sterilized by heat died one of two distinct modes of death. A "rapid" mode, which predominated during the first few days postheating, was characterized by cell detachment and inhibited rates of protein, RNA, and DNA synthesis. A "slow" mode of death became evident after the cells had fully recovered from the heat-induced inhibition of macromolecular synthesis and cell detachment had ceased. These populations had reduced plating efficiencies relative to nonheated populations and contained a large fraction of cells with multiple nuclei. The multinucleated cells did not form colonies, but heated populations also contained increased numbers of uninucleated cells which were nonclonogenic. As the heat dose was increased and the surviving fraction decreased, the rapid mode of death predominated. These data show that heat damage is expressed in two distinct ways. This might result from the existence of two separate targets for heat killing, or a single target which manifests its effects in different ways as the damage it sustains increases.
The circulating catecholamine adrenaline effectively suppressed human natural killer cell cytotoxicity (NKCC) when added to mixtures of effector lymphocytes and 51Cr-labelled target cells in a 4-hour 51Cr release assay in vitro. The effect was mimicked by the beta 2-receptor agonist terbutaline but not by the beta 1-receptor agonist prenalterol or the alpha 1/alpha 2-receptor agonist clonidine. Adrenaline-induced NKCC suppression was completely and potently antagonized by the mixed beta 1/beta 2-receptor antagonist propranolol and the selective beta 2-receptor antagonist ICI 118,551 but not by the beta 1-selective antagonist metoprolol. By comparing the adrenaline sensitivity of high-density (HD) and low-density (LD) lymphocytes, fractionated by Percoll density gradient centrifugation, we found that HD cells appeared more sensitive to adrenaline-induced suppression than LD cells. In both types of effector cells, adrenaline significantly suppressed NKCC at a final concentration of 10(-11) M. Pretreatment of LD effector cells with IFN-alpha reduced the NKCC suppression by subsequent adrenaline treatment. Pretreatment with recombinant IL-2 virtually abolished the response to adrenaline. This effect was noted also when IL-2 and adrenaline were incubated simultaneously during the 4-hour 51Cr release assay. Our data suggest a role for adrenaline, via lymphocyte beta 2-receptor activation, in the regulation of natural killer cells.
It has been previously reported that sauna-induced fevers (approximately 39 degrees C) result in rises of beta-endorphins in normal volunteers. This report describes changes in plasma beta-endorphins in cancer patients undergoing whole body hyperthermia (40.5 degrees C to 41.8 degrees C). Results presented show that there is a linear relationship between thermal stress, defined in terms of core temperature and/or duration of hyperthermia, and the quantitative rise in plasma beta-endorphin levels. Data relating to changes in ACTH and cortisol levels are in a single temperature range (41.5 degrees C--41.8 degrees C) are also reported.
A phase I study of whole body hyperthermia (WBH) (52 treatments/12 patients) utilizing a radiant heat device has been completed. This study incorporated a temperature escalation scheme from 39.5 to 41.8 degrees C for up to 150 min. Pain relief or a sense of well being was observed post-WBH in the first three patients entered in this study. We postulated that WBH might result in increases in the opiate peptide beta-endorphin. Therefore we elected to study prospectively the next six patients entered in this study to test the hypothesis that WBH stimulates the neuroendocrine axis. Results are reported which show thermal-induced increases in plasma levels of beta-endorphin as well as prolactin, ACTH and cortisol.
Natural killer (NK) cells, a subset of lymphocytes, have the ability preferentially to kill virus-infected cells and certain tumor cells in vitro (Herberman et al. 1979). NK cells have been proposed to represent a first level defense mechanism against tumor development and tumor spread in vivo (Herberman 1981; Pollack and Hallenbeck 1982). A correlation between defective NK activity and an increased incidence of malignant disease both in man and in mice supports this concept (Haliotis et al. 1980; Talmadge et al. 1980).
Murine NG108-15 neuroblastoma cells were heated for times of 5-40 min at 45.5 degrees C, and survival ranged from 0.7-0.0015, respectively. Ion-sensitive microelectrodes (ISM) were used to measure the free intracellular concentrations of Cl- and K+ immediately after heating and up to 30 hr later. The free intracellular Cl- and K+ concentrations, [Cl-]i and [K+]i respectively, of the heated cells remained identical to those of the controls for the first 10 hr after heating. At later times, some cells had increased [Cl-]i values and decreased [K+]i values identical to those of the extracellular medium. These cells had a mottled morphology, no longer excluded the vital stain trypan blue, and had no membrane potential. The number of these dye-including, physiologically dead cells increased with time, and was always greater following longer heating times. No changes in mean cellular volume were observed until 25 hr after heating. All trypan-blue-excluding, physiologically live cells had the same [Cl-]i and [K+]i as the control cells, even when the majority of them were destined for clonogenic death.
Heating synchronous G1 cells at 45.5 degrees C for 3-20 min induced varying degrees of membrane blebbing ranging from nonblebbed cells indistinguishable from control cells to those with blebs larger than the cell itself. Both the proportion of cells exhibiting blebbing and the mean diameter of the blebs increased with heating duration. Scoring individual cells for both blebbing and colony formation demonstrated that cells with blebs larger than 50% of the cell diameter did not survive to form colonies. Electron microscopy showed that all subcellular organelles, save the ribosomes, were absent from the membrane blebs. Freeze fracture replicas revealed no changes in membrane ultrastructure, except on some 15% of the blebs that contained bald patches devoid of membrane particles.
Cardiovascular studies were carried out on patients subjected to whole body hyperthermia treatment for advanced malignancy in order to assess the magnitude of the changes occurring and the degree of strain imposed on the system. The subjects, who were anaesthetised with a nitrous oxide/oxygen and relaxant sequence, were heated in a modified Siemens hyperthermia cabin and maintained at a body temperature of 41.8 degrees C for 2 h. The results of 30 treatments are presented. Large increases in cardiac output and heart rate were accompanied by large decreases in peripheral resistance in both the systemic and pulmonary vascular beds. The pulmonary arterial pressure rose whereas that in the systemic circulation fell. This caused right ventricular work to increase proportionately more than left ventricular work. Care should be exercised when subjecting patients with limited right ventricular function to this treatment.
The present study demonstrates that human natural killer (NK) cells isolated from peripheral blood of normal individuals are highly sensitive to hyperthermia. The effect was time and dose dependent, and treatment of peripheral blood lymphocytes at 42 degrees for 1 hr almost completely abolished NK activity. The effect was not a consequence of cell death since only a small decrease in cell viability was observed and the viability of density gradient fractions enriched for NK activity was normal. Analysis of NK activity at the single-cell level by application of a conjugation assay in agarose revealed that hyperthermia interfered with target cell binding as well as the lytic cycle. Attempts to rescue NK activity after hyperthermia treatment by incubation overnight with human alpha-interferon or activation in mixed leukocyte culture was unsuccessful, indicating that even pre-NK cells are heat sensitive. In contrast, the proliferative response to alloantigens in mixed leukocyte culture and to the T-cell mitogen concanavalin A was unaffected. Hyperthermia exposure of cytotoxic T-lymphocyte generated in mixed leukocyte culture immediately before assay against allogeneic blast cells strongly inhibited their activity. Some alterations in the kinetics of stimulation with the B-cell mitogen Staphylococcus aureus bacteria were observed after heat exposure although maximal stimulation was at control levels. Thus, NK cells, including their precursors, seem to be preferentially sensitive to hyperthermia among various lymphoid subclasses.
Whole body hyperthermia (WBH) not only embraces lymphocyte migration to the bone marrow and skin, but also prolongs their subsequent transit through these organs, while inhibiting homing to the lymphoid organs. The effect of WBH is transitory, it subsides within 16 h after a 8 h WBH period. The accumulation of circulating lymphocytes in lymph nodes, Payer's patches and spleen dropped significantly between 4 h and 8 h in WBH, but rose during subsequent 16 h normothermia. In the absence of the adrenal glands, the enhanced bone marrow localization observed in non-adrenalectomised rats during WBH did not occur. Skin localization increased while splenic localization fell in adrenalectomised as compared to non-adrenalectomised rats. These results strongly support the hypothesis that WBH-induced enhancement of lymphocyte migration to the bone marrow is adrenal-hormone dependent. The above mentioned changes can not be attributed to changes in blood flow to the tissues during WBH. Blood flow to the bone marrow was not significantly different from flow to this organ in normothermic rats. Flow to the skin fell significantly and yet localization in this tissue during WBH was higher than during normothermia.
Primary and secondary lymphoid organs are innervated extensively by noradrenergic sympathetic nerve fibers. Lymphocytes, macrophages, and other cells of the immune system bear functional adrenoreceptors. Norepinephrine fulfills criteria for neurotransmission with cells of the immune system as targets. In vitro, adrenergic agonists can modulate all aspects of an immune response (initiative, proliferative, and effector phases), altering such functions as cytokine production, lymphocyte proliferation, and antibody secretion. In vivo, chemical sympathectomy suppresses cell-mediated (T helper-1) responses, and may enhance antibody (T helper-2) responses. Noradrenergic innervation of spleen and lymph nodes is diminished progressively during aging, a time when cell-mediated immune function also is suppressed. In animal models of autoimmune disease, sympathetic innervation is reduced prior to onset of disease symptoms, and chemical sympathectomy can exacerbate disease severity. These findings illustrate the importance of the sympathetic nervous system in modulating immune function under normal and disease states.
Purpose:
To determine whether hyperthermia is to the benefit or detriment of host immune function, the effect of hyperthermia was evaluated on various functions of T-lymphocytes from human umbilical cord blood and compared to that of adult blood.
Methods and materials:
Nonadherent mononuclear cells from cord blood or adult blood were used as the effector cells. To generate lymphokine activated killer (LAK) cells, effector cells were kept in culture for 5 days in complete medium containing recombinant human interleukin-2. To activate effector cells to become cytotoxic, cells were kept in culture in complete medium containing Con A. Cytotoxicity was determined in a standard 4-h chromium release assay using K-562 human erythroleukemic cells (in the natural killer cell activity assay) or Daudi cells (in the LAK cell activity or Lectin dependent cytotoxicity assay) as targets. For heat effects, cells in complete medium were heated at the desired temperature in a water bath for 1 h.
Results:
Lymphokine-activated killer cell activity, lectin-dependent cytotoxicity and T-cell proliferative capacity were not deficient in human cord blood. Cytotoxic activities of T-cells from adult blood as well as from cord blood can be enhanced at febrile range (< or = 40 degrees C), and were significantly decreased by exposure to 1 h at 42 degrees C.
Conclusion:
The febrile responses (< or = 40 degrees C) to infection, in the course of malignant disease and with biological response modifiers treatment, may all be related to host defense mechanisms. Based on these observations, whole body hyperthermia (< or = 40 degrees C), in combination with the appropriate cytokines, may have therapeutic potential in the treatment of neonatal infections and malignancies under certain circumstances. Hyperthermia in febrile range may, therefore, confer an important immunoregulatory advantage to the host. In contrast, tumor killing therapeutic temperature (> 42 degrees C) which inhibits host immunocompetence should probably be used only for local hyperthermia.
Natural cytotoxicity, mediated by natural killer (NK) cells and cell with lymphokine-activated killer (LAK) activity, is believed to play an important role in host anti-cancer mechanisms.
The authors critically review recent publications on the role of natural cytotoxicity in patients with cancer.
In patients with cancer, several studies have noted variations in the numbers and activity of NK and cells with LAK activity in different body compartments. NK cell activity in the peripheral blood lymphocytes (PBLs) is higher than that found in lymph nodes and within tumors, and this appears to be due to the presence of suppressor factors. The natural cytotoxicity of PBLs in patients with different types of cancers varies. However, there appears to be a trend for natural cytotoxicity to be reduced in certain cancer patients, possibly related to tumor volume or dissemination. Anti-cancer treatments (e.g., surgery, hormonal modulation, radiotherapy and chemotherapy) can also result in suppression of natural cytotoxicity, although the long-term effect on response to treatment and development of metastases is at present unknown.
NK and LAK cells, through the use of immune biologic modifiers, have been demonstrated to have a therapeutic role in the treatment of human cancers. Further studies are required to determine the optimal dosages and combinations of chemotherapeutic agents, the timing of surgery, and the adjuvant use of immune biologic response modifiers. An increasing awareness and understanding of this field, may allow for the future development of anti-cancer therapies.
The numbers and proportions of leukocytes in the blood provide an important representation of the state of activation of the immune system, and of the pattern of distribution of immune cells in the body. We have shown previously that acute stress induces large, rapid, and reversible changes in the distribution of peripheral blood leukocyte subpopulations in the rat. The studies described here specifically investigate the role played by adrenal steroid hormones in mediating stress-induced changes in blood leukocyte distribution. Since adrenal steroids act at two distinct receptor subtypes that show a heterogeneity of expression in immune cells and tissues, the role played by each subtype in mediating changes in leukocyte distribution is also investigated. Cyanoketone, a corticosterone (CORT) synthesis inhibitor, significantly reduced the decrease in lymphocyte numbers observed during stress and significantly enhanced the increase in neutrophil numbers observed after the cessation of stress. Acute administration of aldosterone (a specific type I adrenal steroid receptor agonist) to adrenalectomized animals did not have a significant effect on blood leukocyte numbers. In contrast, acute administration of CORT (the endogenous type I and type II receptor agonist), or RU28362 (a specific type II receptor agonist), to adrenalectomized animals produced changes in leukocyte distribution that were similar to those observed in intact animals during stress. These results suggest that CORT, acting at the type II adrenal steroid receptor, is a major mediator of the stress-induced changes in blood lymphocyte and monocyte distribution.
The levels of TNF, IL-1 and IL-6 in circulating blood female WAG/Ry rats were assessed in relation to treatment with localized hyperthermia of the right hind leg or with whole-body hyperthermia (WBH). After a localized treatment for 30 min at 43 or 44 degrees C no detectable increase in levels of IL-6 or TNF was obtained. Hyperthermia for 30 min at 45 degrees C led to an elevated level of IL-6 of 19.4 +/- 5.2 U/ml above the control level of 24 h after treatment. Levels of IL-1 were never higher than those in control animals that received only anaesthesia. Anaesthesia induced a peak level of approximately 131 U/ml IL-1 6 h after treatment. Serum levels of IL-1 and IL-6 are enhanced after WBH. IL-1 reaches a peak level already during WBH about 15 after reaching 41.5 degrees C. IL-6 levels were not enhanced during WBH but 1 h after WBH a clear peak was observed. Anaesthesia with sham WBH did not lead to enhanced IL-6 levels but enhanced IL-1 levels were clearly detected. We did not detect TNF in any sample after WBH. It is concluded from the present results that IL-6 is not induced by a 'standard' treatment of localized hyperthermia as used in oncotherapy (i.e. 60 min at 43 degrees C) to such a high level locally that this is reflected in increased levels in circulating blood. WBH at clinically relevant temperatures leads to enhanced levels of IL-1 and IL-6. The difference in IL-6 response after WBH or localized hyperthermia probably is related to the fact that in WBH also the bone marrow is treated. This may lead to stimulation of this important stem cell compartment of the peripheral blood. The sequence of appearance of IL-1 and IL-6 after hyperthermia is akin to the sequence in an inflammatory response. However, the experiments with sham treatment show that IL-1 may appear in the circulating blood not followed by IL-6. These results indicate that enhanced IL-1 levels may reflect a stress reaction of the animal related to the (sham) treatment. Enhanced levels of IL-1 after WBH correlate with enhanced levels of ACTH in the circulating blood.
High-dose steroid pulse therapy is effective in transplant rejection and severe autoimmune diseases. Our goal was to identify the mechanism by which high-dose steroid exerts specific immunosuppressive actions. In this study, we investigated the in vivo effects of high-dose (1 g) methylprednisolone infusion on peripheral blood T lymphocyte apoptosis induction in 15 patients with severe autoimmune diseases. DNA fragmentation was detected in peripheral blood T cells isolated from these patients after 2 and 4 hr of steroid infusion. In contrast, T cells isolated from the same patients before or 8 or more hours after infusion did not show DNA fragmentation. DNA fragmentation was more significant in CD4+ than CD8+ T cells. The susceptibility of CD4+ T cells to apoptosis was associated with a lower expression of Bcl-2 in these cells compared with that on CD8+ T cells. To support the T-cell apoptosis induction by pulse therapy, peripheral blood T cells from normal subjects underwent DNA fragmentation after in vitro exposure to 2.5-10 microg/ml of methylprednisolone for 30 min. Our results indicate that induction of peripheral blood T-cell apoptosis is an important mechanism contributing to the immunosuppression observed after high-dose steroid therapy.
Tricyclic antidepressants (TCAs) have been shown to induce apoptosis in human lymphocytes. In the present report, we investigated in parallel the regulation of the three oncogenes bcl-2, c-myc, and Fas. A reduction in c-myc and bcl-2 levels of 35–40% and 22–27%, respectively, was observed. On the other hand, Fas expression on the outer surface of the plasma membrane was increased up to 31%. In conclusion, bcl-2, c-myc, and Fas are undergoing dysregulation due to TCA-induced apoptosis. © 1997 John Wiley & Sons, Inc.
To determine if heat exposure alters the hormonal responses to moderate, repeated exercise, 11 healthy male subjects [age = 27.1 (3.0) years; maximal oxygen consumption, VO2max = 47.6 (6.2) ml x kg x min(-1); mean (SD)] were assigned to four different experimental conditions according to a randomized-block design. While in a thermoneutral (23 degrees C) or heated (40 degrees C, 30% relative humidity) climatic chamber, subjects performed either cycle ergometer exercise (two 30-min bouts at approximately 50% VO2max, separated by a 45-min recovery interval, CEx and HEx conditions), or remained seated for 3 h (CS and HS conditions). Blood samples were analyzed for various exercise stress hormones [epinephrine (E), norepinephrine (NE), dopamine, cortisol and human growth hormone (hGH)]. Passive heating did not alter the concentrations of any of these hormones significantly. During both environmental conditions, exercise induced significant (P < 0.001) elevations in plasma E, NE and hGH levels. At 23 degrees C during bout 1: E = 393 (199) pmol x l(-1) (CEx) vs 174 (85) pmol x l(-1) (CS), NE = 4593 (2640) pmol x l(-1) (CEx) vs 1548 (505) pmol x l(-1) (CS), and hGH = 274 (340) pmol x l(-1) (CEx)vs 64 (112) pmol x l(-1) (CS). At 40 degrees C, bout 1: E = 596 (346) pmol x l(-1) (HEx) vs 323 (181) pmol x l(-1) (HS), NE = 7789 (5129) pmol x l(-1) (HEx) vs 1527 (605) pmol x l(-1) (HS), and hGH = 453 (494) pmol x l(-1) (HEx) vs 172 (355) pmol x l(-1) (HS). However, concentrations of plasma cortisol were increased only in response to exercise in the heat [HEx = 364 (168) nmol x l(-1) vs HS = 295 (114) nmol x l(-1)]. Compared to exercise at room temperature, plasma levels of E, NE and cortisol were all higher during exercise in the heat (P < 0.001 in all cases). The repetition of exercise did not significantly alter the pattern of change in cortisol or hGH levels in either environmental condition. However, repetition of exercise in the heat increased circulatory and psychological stress, with significantly (P < 0.001) higher plasma concentrations of E and NE. These results indicate a differential response of the various stress hormones to heat exposure and repeated moderate exercise.
To evaluate stress-induced changes in blood leukocytes with emphasis on the natural killer (NK) cells, eight male volunteers were followed during three trials of head-up tilt with adrenergic beta 1- (metoprolol) and beta 1 + 2- (propranolol) blockade and with saline (control) infusions. The beta 1- and beta 1 + 2-receptor blockade did not affect the appearance of presyncopal symptoms, but the head-up tilt induced a transient lymphocytosis that was abolished by beta 1 + 2-receptor blockade but not by beta 1-receptor blockade. Head-up tilt also resulted in delayed neutrophilia, which was insensitive to beta-receptor blockade. Lymphocyte subset analysis revealed that the head-up tilt resulted in a twofold increase in the percentage and absolute number of CD3-/CD16+ and CD3-/CD56+ NK cells in peripheral blood and that this increase was partially blocked by metoprolol and abolished by propranolol. The NK cell activity on a per NK cell basis did not change during head-up tilt, indicating that the cytotoxic capability of NK cells recruited to circulation is unchanged. The data suggest that the head-up tilt-induced lymphocytosis was due mainly to CD16+ and CD56+ NK cells and that their recruitment to the blood was inhibited by beta 1- and especially beta 1 + 2-receptor blockade. Thus stress-induced recruitment of lymphocytes, and of NK cells in particular, is mediated by epinephrine through activation of beta-receptors on the lymphocytes.
Both T cells and natural killer (NK) cells express CD2, the target of an alternative activation pathway that induces the proliferation of both cell types. The mitogenic response to CD2 ligation requires the co-expression of CD3:TCR in T cells and FcgammaRIII in NK cells, suggesting that these receptors are involved in transducing the response initiated by CD2. The ability of FcgammaRIII to trigger the activation-induced death of IL-2-primed NK cells led us to investigate the potential for CD2 to trigger activation-induced NK cell death. Our results reveal that the same anti-CD2 monoclonal antibodies (mAb) that activate freshly isolated NK cells induce apoptosis in IL-2-primed NK cells. CD2-induced apoptosis results in chromatin condensation, DNA fragmentation and cleavage of caspase-3. Activation-induced NK cell death triggered by CD2 ligation is extremely rapid (DNA fragmentation is first observed at 90 min) and it is not inhibited by neutralizing antibodies reactive with TNF-alpha or Fas ligand. Whereas mAb reactive with distinct CD2 epitopes (i.e. T11.1, T11.2, and T11.3) are required for activation-induced T cell death, mAb reactive with a single CD2 epitope are sufficient for activation-induced NK cell death. The ability of CD2, CD16, and CD94 to induce apoptosis in IL-2-primed lymphocytes suggests that cytokine priming changes the response to a signaling cascade that is common to each of these activation receptors.
When mice were physically restrained in 50-ml tubes for 24 h, a marked decrease of NK activity was demonstrated in parallel with the elevation of serum corticosterone levels. The release of mice from restraint stress resulted in the recovery of NK activity, with a decrease of serum corticosterone levels within 48 h. Using this stress model, we also investigated the influence of restraint stress on mouse Th1/Th2 balance. Consistent with the decrease of NK activity, IFN-gamma production of mouse spleen cells greatly reduced after suffering from restraint stress. In contrast, the IL-4 producing ability of spleen cells was not so much affected by restraint stress. These results initially indicated that stress may induce the skewing of the Th1/Th2 balance toward Th2-dominant immunity, which stimulates the occurrence of infectious diseases and allergic disorders.
A single treatment of low-temperature, long-duration, whole-body hyperthermia of either severe combined immunodeficient (SCID) mice bearing human breast tumor xenografts or Balb/c mice bearing syngeneic tumors for 6-8 hr can cause a temporary reduction of tumor volume and/or a growth delay. In both animal model systems, this inhibition is correlated with the appearance of large numbers of apoptotic tumor cells. Because this type of mild heat exposure, comparable to a common fever, is not itself directly cytotoxic, other explanations for the observed tumor cell death were considered. Our data support the hypothesis that this hyperthermia protocol stimulates some component(s) of the immune response, which results in increased antitumor activity. In support of this hypothesis, increased numbers of lymphocyte-like cells, macrophages, and granulocytes are observed in the tumor vasculature and in the tumor stroma immediately following this mild hyperthermia exposure. In Balb/c mice, an infiltrate persists in the tumor for at least 2 weeks. Using the SCID mouse/human tumor system, we found that both host natural killer (NK) cells and injected human NK cells were increased at the site of tumor following hyperthermia treatment. Experiments using anti-asialo-GM1 antibodies indicate that the tumor cell apoptosis seen in the SCID mouse appears to be due largely to the activity of NK cells, although additional roles for other immunoeffector cells and cytokines appear likely in the immunologically complete Balb/c model. Another interrelated hypothesis is that immunoeffector cells may have greater access to the interior of the tumor because we have observed that this treatment causes an obvious expansion in the diameter of blood vessels within the tumor and an increase in nucleated blood cells within the vessels, which persists as long as 2 weeks after treatment. Further study of the mechanisms by which mild hyperthermia exerts antitumor activity could result in this treatment protocol being used as an effective, nontoxic adjuvant to immunotherapy and/or other cancer therapies.