Article

In vitro Immunoreactivity towards Lectin-rich or Viscotoxin-rich Mistletoe (Viscum album L.) Extracts Iscador Applied to Healthy Individuals

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Abstract

In-vitro-Immunreaktion gegen Lektin-reiche und Viscotoxin-reiche Mistel (Viscum album L.)-Extrakte Iscador nach Verabreichung an gesunde Probanden / Eine randomisierte doppelblinde Plazebo-kon-trollierte Studie Ziel der Studie war festzustellen, wie die Exposition mit Mistelextrakten die zellulären Immunreaktionen durch mononukleäre Zellen im peripheren Blut (PBMC) gesunder Probanden beeinflusst. 47 gesunde Probanden wurden zwölf Wochen entweder mit Iscador® Quercus spezial (IQ; reich an Mistellektin [ML]) (n = 16), Iscador Pinus (IP; arm an ML, aber reich an Viscotoxin) (n = 15) oder Plazebo (physiologische Kochsalzlösung) (n = 16) behandelt. Die PBMC wurden vor der Exposition, während der Exposition in Woche 4, 8 und 12 sowie 13 Wochen nach der letzten Exposition isoliert und 7 Tage lang mit IQ oder IP inkubiert. Es wurde die Proliferation und die Zytokin-Freisetzung bestimmt (Typ 1-Zytokine: Interferon [IFN]-y, Tumornekrosefaktor [TNF]-ß, Typ 2-Zytokine: Interleukin [IL]-5, IL-13, Makrophagen-/Monozyten-Zytokine: IL-1, TNFa). Die Inkubation der PBMC von nicht exponierten Individuen mit IP und IQ führte zu einem signifikanten Anstieg der Proliferation und der Produktion aller Zytokine. Es fand sich im Vergleich zu Plazebo ein signifikanter Anstieg der IQ-induzierten TNFα- (aber nicht IL-2-) Produktion durch PBMC in Woche 25 bei Probanden, die IQ erhalten hatten (p < 0.05). In der IP-Gruppe nahm die Produktion der Typ-2-Zytokine IL-5 und IL-13 signifikant ab (p < 0.05 im Vergleich zu Plazebo in Woche 8). Diese Daten zeigen, daß IP ein Antigen zu enthalten scheint, welches die Typ 2-Reaktivität senkt. Außerdem scheint ein Bestandteil, der bevorzugt in IQ vorhanden ist, die Produktion des Monozy-ten-/Makrophagen-abhängigen Zytokins TNFα durch PBMC zu aktivieren. Interessant ist, dass auch bei Probanden, bei denen Plazebo injiziert wurde, während des Beobachtungszeitraums immunologische Veränderungen zu beobachten waren.

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... similar results have been obtained previously when different mistletoe extracts were applied to PBMC. 9,10,21,28 In a study by stein et al, a fermented mistletoe extract from the host tree pine was found to be the only extract out of six tested which was capable to induce cell proliferation in PBMC of mistletoe naive individuals, supporting our present results. 21 huber et al revealed a significant increase of the proliferative response by PBMC after stimulation with mistletoe extracts from the host trees pine or oak in vivo and in vitro. ...
... 21 huber et al revealed a significant increase of the proliferative response by PBMC after stimulation with mistletoe extracts from the host trees pine or oak in vivo and in vitro. 28 Furthermore, a strong increase in the production of macrophage/monocyte related and T helper type 1 and type 2 related cytokines was observed. similarly, a stimulatory effect was observed in PBMC treated with an extract of mistletoe grown on poplar. ...
... huber et al postulated the existence of either natural immunity toward components of mistletoe extract acting as "recall antigens" or of some mitogenic activity of mistletoe components as possible underlying effects for the stimulation of PBMC. 28 Another disparity of the mistletoe impact on PBMC and Jurkat might be due in part to the difference in the low innate prolifera-tive activity of resting PBMC and the fast dividing cancer cells. Indeed, mistletoe extract was shown not to affect proliferation of rapidly proliferating amniotic fluid cells, 35 supporting the hypothesis that its stimulating effect is limited to slowly proliferating cells. ...
... The cell death of tumour cells is a result of a dose dependent apoptosis (Janssen et al. 1993;Lavastre et al. 2002) (induced by lectins) or necrosis (induced by viscotoxins) (Bussing et al. 1999;Mossalayi et al. 2006). At low dosages (Thies et al. 2007), VAE modulate the function of a number of immunological effectors cells (Beuth et al. 1994;Huber et al. 2006). In vitro and in vivo studies have demonstrated activation of macrophages, natural killer cells (Tabiasco et al. 2002), granulocytes and B-and T-lymphocytes (Fischer et al. 1997;, which is associated with the release of interleukins, tumour necrosis factor-α and interferon γ (Eggenschwiler et al. 2006). ...
... The very low recurrence rate after administration of Iscador® P likely underlines the observation that successful immunotherapy is associated with long-term effects on ES development (Kinnunen et al. 1999). The mechanism of action (Heinzerling et al. 2006) of the mistletoe extract are thought to be based on mistletoes lectins and viscotoxins acting at high concentrations by direct cytotoxic inhibition of the tumour growth (Kovacs et al. 2006) and at low (Thies et al. 2007) dosages as immunostimulation (Beuth et al. 1994;Huber et al. 2006). Iscador® P contains less viscotoxin and lectines than the other preparations (Urech et al. 2006), so in this study the mistletoe extract was applied at low dosage as immunotherapy. ...
... The phagocytosis rate, as well as the cell cytotoxicity of the cells of the non-specific immune system can be increased by treatment with mistletoe extracts [95]. Thus, mistletoe lectins can stimulate the production of granulocyte/macrophage colony-stimulating factor (GM-CSF) by mononuclear cells in the peripheral blood, thus activating granulocytes and monocytes in the bone marrow [96]. Based on viscotoxin-dependent and viscotoxin-independent mechanisms, in vitro studies showed stimulation of granulocyte activity [97]. ...
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Modern phytotherapy is part of today’s conventional evidence-based medicine and the use of phytopharmaceuticals in integrative oncology is becoming increasingly popular. Approximately 40% of users of such phytopharmaceuticals are tumour patients. The present review provides an overview of the most important plants and nature-based compounds used in integrative oncology and illustrates their pharmacological potential in preclinical and clinical settings. A selection of promising anti-tumour plants and ingredients was made on the basis of scientific evidence and therapeutic practical relevance and included Boswellia, gingko, ginseng, ginger, and curcumin. In addition to these nominees, there is a large number of other interesting plants and plant ingredients that can be considered for the treatment of cancer diseases or for the treatment of tumour or tumour therapy-associated symptoms. Side effects and interactions are included in the discussion. However, with the regular and intended use of phytopharmaceuticals, the occurrence of adverse side effects is rather rare. Overall, the use of defined phytopharmaceuticals is recommended in the context of a rational integrative oncology approach.
... VA preparations are complex multicomponent mixtures with numerous constituents and multiple anti-carcinogenic effects, and can be applied as subcutaneous and off-label intravenous, intratumoral, and intracavitary injections [12]. VA extracts mediate numerous antitumour, pro-apoptotic, anti-proliferative, and immunomodulatory effects and are involved in processes of DNA stabilization and repair as well as in the reduction of chromosomal damage [13][14][15][16][17][18][19][20]. Research into these mechanisms has been indicative for VA extracts being among the best-studied plant extracts [21]. ...
Article
Background: A majority of oncological patients apply add-on white-berry European mistletoe (Viscum album L., VA) extracts to reduce disease- and treatment-related symptoms and to improve health-related quality (HRQL) of life. VA extracts exert various antitumor, pro-apoptotic, anti-proliferative and immunomodulatory effects. Two current meta-analyses attribute life-prolonging and HRQL improving properties to additive VA therapy. The aim of the study present update was to review the current knowledge on VA extracts in clinical oncology. Hereby, we concentrated on studies with the highest clinical relevance in the field of lung, gastric, colorectal and pancreatic, gynaecological and breast cancer applying the anthroposophical mistletoe preparations. Summary: The present update provides a brief overview regarding the use of VA preparations in clinical oncology reviewing current guidelines, systematic reviews, randomized controlled and real-world data studies. We have searched the pubmed.gov database of the National Library of Medicine with the search terms «mistletoe» and «cancer». We found a good evidence of add-on VA therapy to improve the HRQL of patients with breast cancer (American Society of Clinical Oncology - endorsed Society for Integrative Oncology guideline) and of HRQL-improving and survival-prolonging properties of VA therapy in pancreatic cancer. In the field of gastrointestinal, gynaecological and lung cancer, new or updating integrative and/or oncological guidelines should consider clear recommendations on integrative therapies including VA therapy. Nevertheless, further clinical and real-world data trials need to be performed in this field. Key messages: • Evidence for add-on VA treatment for the the improved management of cancer and cancer-related side effects is accumulating • Patients with breast cancer: good evidence for add-on VA therapy to improve the HRQL of oncological patients • Patients with pancreatic cancer: good evidence for add-on VA to improve HRQL and prolong survival • Patients with gastrointestinal, gynaecological and lung cancer: update of guidelines is recommended with regards to integrative oncological therapies including add-on VA.
... In oncology, the complementary therapy with VA extracts is among the most common integrative therapies used in German-speaking European countries and the daily dose prescription of VA preparations rank ahead of several oncological drugs such as carboplatin, nivolumab, pembrolizumab and pemetrexed [12]. VA extracts mediate numerous antitumor, antiapoptotic, anti-proliferative and immunomodulatory effects and are involved in processes of DNA stabilization and repair as well as in the reduction of chromosomal damage [13][14][15][16][17][18][19][20]. Research into these mechanisms has been indicative for VA extracts being among the best-studied plant extracts [21]. ...
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Aim: A majority of oncological patients apply add-on white-berry European mistletoe (Viscum album L., VA) extracts to reduce disease-and treatment-related symptoms and to improve health-related quality (HRQL) of life. VA extracts exert various antitumor, pro-apoptotic, anti-proliferative and immunomodulatory effects. Two current meta-analyses attribute life-prolonging and HRQL improving properties to additive VA therapy. The aim of the study was to review the current knowledge on VA extracts in clinical oncology. Methods: 290 clinical research articles including systematic reviews and guidelines were screened and analysed for their association with add-on VA therapy in patients with gynaecological, lung or gastrointestinal cancer. Results: We found a good evidence of add-on VA therapy to improve the HRQL of patients with breast cancer (ASCO-endorsed SIO guideline) and of HRQL-improving and survival-prolonging properties of VA therapy in pancreatic cancer. In the field of gastrointestinal, gynaecological and lung cancer, new or updating integrative and/or oncological guidelines should consider clear recommendations on integrative therapies including VA therapy. Nevertheless, further clinical and real-world data trials need to be performed in this field. Conclusion: The present update provides a brief overview regarding the use of VA preparations in clinical oncology reviewing current systematic reviews, randomized controlled and real-world data studies. In addition, current guidelines as to their suggestions in the context of VA therapy are highlighted as evidence in the improved management of cancer and cancer-related side effects for this treatment is accumulating.
... They all contain substances like mistletoe lectins or viscotoxins with cytotoxic and immunodulatory properties. 2,3 In some hospitals and outpatient clinics in Germany and Switzerland, mistletoe preparations (MPs) are also used off-label intravenously in cancer patients within treatment concepts of anthroposophic medicine. 4 Since the 1920s, induction of fever is regarded as favorable for cancer patients from the viewpoint of anthroposophic medicine, and infusions of MPs are often used to induce fever. ...
Article
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Purpose: So-called spontaneous remissions in cancer often seem to occur after febrile events. Mistletoe preparations (MPs) are used off-label intravenously to induce fever within concepts of integrative oncology. We wanted to investigate the frequency of febrile reactions and safety related to intravenously applied MPs (IAMPs). Methods: This was a retrospective analysis of data from consecutive cancer patients who were treated in 2 anthroposophic hospitals with IAMPs. The main outcome parameter was the rate of core temperature increase to ≥38.5°C within 24 hours after IAMPs. Secondary outcome parameters were Common Toxicity Criteria for Adverse Events (CTCAE; version 4.0). Results: 59 patients, with in total 567 IAMPs, were analyzed; 45 patients (76%, 95% CI = 65%-87%) had an increase of core temperature to ≥38.5°C after at least 1 treatment. Mean increase in temperature was 1.5°C ± 0.8°C. Adverse events were mostly fever-related symptoms (headache, joint pain, shivering). Grade 1 allergic reactions were documented in 0.6% of treatments. CTCAEs grade 3 to 5 did not occur; 38/59 patients had advanced and/or metastatic disease. Conclusion: IAMPs resulted in febrile reactions to >38.5°C in the majority of patients and can be considered as safe. Adverse events were mostly related to fever and were not severe.
... Mistletoe extracts have been shown to kill cancer cells in vitro and can stimulate immune system cells both in vitro and in vivo [5][6][7]. Two components of mistletoe, namely, viscotoxins and lectins, have been shown to be largely responsible for these effects [7][8][9]. Reports on the clinical efficacy of mistletoe therapy have been conflicting and systematic 2 Evidence-Based Complementary and Alternative Medicine literature reviews often criticise studies for poor design [10,11]. Although an effect of mistletoe on tumour shrinkage in vivo or overall survival might remain to be proven more thoroughly, a growing number of studies indicate beneficial effects on quality of life of cancer patients and reduction of adverse drug reactions (ADRs) associated with conventional cancer treatments [12][13][14][15][16][17]. ...
... Mistletoe extracts have been shown to kill cancer cells in vitro and can stimulate immune system cells both in vitro and in vivo [5][6][7]. Two components of mistletoe, namely, viscotoxins and lectins, have been shown to be largely responsible for these effects [7][8][9]. Reports on the clinical efficacy of mistletoe therapy have been conflicting and systematic 2 Evidence-Based Complementary and Alternative Medicine literature reviews often criticise studies for poor design [10,11]. Although an effect of mistletoe on tumour shrinkage in vivo or overall survival might remain to be proven more thoroughly, a growing number of studies indicate beneficial effects on quality of life of cancer patients and reduction of adverse drug reactions (ADRs) associated with conventional cancer treatments [12][13][14][15][16][17]. ...
Article
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... Mistletoe extracts have been shown to kill cancer cells in vitro and can stimulate immune system cells both in vitro and in vivo [5][6][7]. Two components of mistletoe, namely, viscotoxins and lectins, have been shown to be largely responsible for these effects [7][8][9]. Reports on the clinical efficacy of mistletoe therapy have been conflicting and systematic 2 Evidence-Based Complementary and Alternative Medicine literature reviews often criticise studies for poor design [10,11]. Although an effect of mistletoe on tumour shrinkage in vivo or overall survival might remain to be proven more thoroughly, a growing number of studies indicate beneficial effects on quality of life of cancer patients and reduction of adverse drug reactions (ADRs) associated with conventional cancer treatments [12][13][14][15][16][17]. ...
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A plant lectin, Viscum album agglutinin-I (VAA-I) has been shown to increase the number and cytotoxic activity of natural killer (NK) cells in animal models, but the mechanisms underlying these effects are poorly understood. We investigated the effects of the recombinant form of this lectin (rVAA) on secretion of interleukin (IL)-12 and on NK-mediated cytotoxicity against K562 target cells in cultures of human peripheral blood mononuclear cells (PBMC) as well as against YAC-1 target cells in cultured rat spleen cells. In 24-hour cultures of PBMC, 10 ng/ml plant VAA-I and 50 ng/ml rVAA induced significant increases in the secretion of total IL-12. Its biologically active heterodimeric form, p70, was also significantly induced by rVAA. Preincubation of PBMC or splenocytes for 48 h with rVAA in concentrations ranging between 10 pg/ml and 100 pg/ml resulted in moderate enhancements of NK-mediated cytotoxicity. However, coincubation of a low dose of rVAA (100 pg/ml) together with IL-2 and IL-12 (60 U/ml and 2 U/ml, respectively) led to additive stimulation of NK activity. In in vivo experiments, rVAA showed an enhancing effect on NK activity with a bell-shaped curve of efficacy. Forty-eight hours after a single intravenous injection of its most effective doses, 0.5 and 1 ng/kg, into Wistar rats, the NK cytotoxicity of splenocytes against YAC-1 targets doubled, and the frequency of large granular lymphocytes in peripheral blood showed 2.1- and 3-fold increases as compared to control animals. Twenty-four hours following these low lectin doses, the number of large granular lymphocytes was also significantly elevated. After 48 h, 0.5 ng/kg rVAA induced a significant augmentation in the percentage of peripheral Mac-1+ mononuclear cells, including activated monocytes and NK cells. The present results suggest that rVAA augments the secretion of an active form of IL-12 and potentiates the cytokine-induced NK activation. These effects of rVAA may be related to its stimulatory effects on MHC-unrestricted cytotoxicity in vivo.
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Injections of non-toxic doses of purified galactoside-specific lectin from the Viscum album plant (VAA-I) caused significant changes in the cellular host defense system in animal models. To establish the immunomodulatory potency of VAA-I on human subjects, four randomized double blind crossover trials were performed on healthy volunteers. In the first and second trials using either older (storage over 8 months at 4°C) or freshly (application immediately after production) isolated lectin enriched preparation from mistletoe extract by ultrafiltration with known VAA-I content, the effect of lectin on the number of CD 3+, CD4+, CD 8+, CD 16+/56+ cells, natural killer cytotoxicity and frequency of large granular lymphocytes was tested in peripheral blood of nine and eight individuals, respectively. In comparison to the significant increase in the number of peripheral lymphocytes observed in balb/c mice, human healthy individuals showed no significant difference between their responses after lectin enriched preparation and saline treatment. Due the considerable intrinsic fluctuation of these parameters in placebo control and the assumption that a change in immunomodulatory potency of VAA-I in lectin enriched preparation depends on aging, a third and fourth double blind trial, in this case using freshly isolated VAA-I from plant, were performed on six and eight healthy volunteers, respectively. In these studies an other more rapidly detectable parameter, the priming of polymorphonuclear (PMN) leukocytes, was monitored. In both studies, 5 h after lectin injection, significant enhancement in priming of circulating PMNs was found compared to the placebo response.
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The humoral response components of an aqueous mistletoe extract (HM) was evaluated in 23 tumor patients who had been treated from 2 months up to 6 years with increasing dosages of HM. IgG antibodies against mistletoe lectin and other components of this extract were detected by ELISA, immunodiffusion, and blotting technique, using either the aqueous extract (HM) or a purified lectin preparation (ML). Their activity depended upon dosage of HM and length of therapy. No anti-HM/ML antibodies of the IgM type could be detected. Immunoblotting revealed lectin-specific antigens at 62 kD, 33k D, and 29 kD. In the presence of ML or HM, PHA-induced proliferation of normal lymphocytes was decreased in a dosedependent manner; this effect was neutralized by adding the IgG fraction from pooled anti-HM-antibody-positive sera, indicating that the cytotoxic effect of lectins was eliminated by these specific antibodies. In view of these findings, it is questionable whether exposing tumor cells to mistletoe extracts in vivo exerts the same direct effect on tumor cells that is observed in vitro.
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Anti-mistletoe lectin-1 (ML-1) antibodies are produced during treatment of cancer patients with mistletoe extracts. However, little is known about their ability to recognise distinct epitopes present in mistletoe extracts. To estimate this, ML-1, ML-2 and ML-3 were analysed by Western blot analysis using high titred anti-ML antibody positive sera from cancer patients treated with different mistletoe extracts. In these experiments we could clearly demonstrate that anti-ML antibodies bind to ML-1 A- and B-chains and, in addition, that they recognised a spectrum of other antigens. This kind of immunological response varied from one individual to another and was not influenced by the different mistletoe extracts. Elution studies showed that anti-ML-1 A-chain or B-chain specific antibodies cross-reacted with A- or B-chains of the other lectins indicating homologies between these molecules (probably in the glycosylated side chain). However, the unglycosylated ML-3 A-chain was only detectable by antibodies specific for the ML-3 A-chain. From our data it has to be concluded that different epitopes of the mistletoe extracts are involved in the induction of the humoral immune response during mistletoe therapy and also that cross-reactivity between the different ML exist.
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There is evidence from recent data that mistletoe extracts exert immunostimulatory properties which could explain their therapeutic effects observed in some tumor patients. Aim of our study was, therefore, to investigate the effect of a subcutaneous 16-weeks therapy with a mistletoe extract (ABNOBAviscum Mali, AM) on the cellular and humoral immune responses in eight breast cancer patients. Mistletoe therapy induced a strong initial proliferation of peripheral blood mononuclear cells (PBMC) in all individuals, which, however, decreased in six patients during the observation period, indicating that not only activating but also inhibitory mechanisms have been induced. In all supernatants of AM-stimulated cell cultures TNF-alpha or IL-6 were found, indicating the activation of cells of the monocyte-/macrophage lineage by mistletoe extracts. Further analyses revealed, that AM induced in vitro also the release of low amounts of IFN-gamma and IL-4 with individual variations. At the end of the therapy, a shift to Th1- related cytokines could be observed in the in vitro cell culture system. All patients produced anti-mistletoe lectin 1 antibodies of the IgG-type during therapy and in four of them additionally antibodies of the IgE-type were found. It, therefore, seems that AM can influence the Th1/Th2 balance and, in case of a Th1 shift, this may favourably influence the tumor growth.
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A peptide isolated from the Viscum album extract (Iscador) has been reported earlier to the both cytotoxic and tumour reducing. Spleen cells from animals treated with a very small quantity of this peptide were found to have increased response to phytohaemagglutinin and Concanavalin-A, indicating that more mature lymphocytes are produced by the peptide administration. Moreover injection of the peptide at the lesion site produced infiltration of lymphocytes and macrophages and finally producing necrosis of the tumor. This peptide also stimulated macrophages in vitro and in vivo and activated macrophages were found to have cytotoxic activity towards L-929 fibroblasts.
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Lymphocytes of 25 patients treated with an aqueous mistletoe extract (Viscum album L.) for up to 6 months (group 1), up to 2 years (group 2), and more than 2 years (group 3) were examined in 3- and 7-day cultures for specifically sensitized lymphocytes. The whole extract (HM), the lectin-polysaccharide fraction (HM-LP), and the ‘viscotoxin’ fraction (HM-V) were added at concentrations ranging from 0.5 μg to 12.5 mg extract/ml. Lymphocytes from four of the nine group 2 patients and five of the ten group 3 patients reacted specifically with HM and HM-LP at an optimal dose of 5.0 mg/ml, but did not react with HM-V. Stimulation indices varied between 1.6 and 16. In the patients of group 3 this effect was observed only when their lymphocytes were costimulated in the 3-day cultures with phytohem-agglutinin (PHA), in contrast to the four patients of group 2 who reacted only in the 7-day cultures with HM-LP without PHA co-stimulation. Patients' lymphocytes had to be protected from mistletoe lectin-induced cytotoxicity by the addition of their own sera containing anti-mistletoe lectin antibodies. Lymphocytes from tumor patients (n=18) never treated with mistletoe extracts and healthy individuals (n=18) showed no specific proliferative response when tested in 3- and 7-day cultures. The production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFN-γ) was measured in the supernatants of lymphocyte cultures from all 25 patients and 36 controls exposed to HM, HM-LP, and HM-V in 3- and 7-day cultures. An increase of GM-CSF (up to 140%) was found only in those patients who responded specifically to the extract, while none of them produced increasing amounts of IFN-γ. These findings imply that a sub-population of T-helper cells may have been stimulated in the course of mistletoe therapy.
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Viscum album extracts (Helixor) were investigated for their potency to influence natural killer cell (NK) cytotoxicity of human peripheral blood mononuclear cells (PBMC) in vitro. The samples investigated were unable to enhance NK cytotoxicity in PBMC/tumor cell co-cultures by direct short-term mediation but NK cytotoxicity of human PBMC was strongly stimulated when PBMC were pre-incubated for 72 h with a partly purified fraction (HM-BP) derived from extracts of V. album mali. Stimulation of NK cytotoxicity was not dependent from age and sex of PBMC donors and was directed against highly as well as moderately NK-sensitive human tumor cells. The responding effector cells were identified as monocytes/macrophages and stimulation of the NK cytotoxicity of these cells was not based on increased proliferation. The active component in the HM-BP fraction has a molecular weight of about 1000 Da or smaller and correlates with the structural criteria of an oligosaccharide. The activity was completely abrogated when the active fraction was treated with endoglycosidase F or alpha-glucosidase. Partial inactivation was observed after treatment with endoglycosidase D or hemicellulase. Moreover, the active fraction induced a reduction in tumor take incidence and tumor development in mice when applied before and after tumor challenge.
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Pancreatic cancer is a devasting disease with poor prognosis. It is characterized by its unresponsiveness to chemo- and/or radiotherapy. Therefore, many patients demand alternative drug therapy such as mistletoe treatment. However, there are no controlled data available analyzing the effect of mistletoe treatment in pancreatic cancer. In the present phase I/II study we evaluated the effect of mistletoe (Eurixor) treatment in 16 patients (7 women, 9 men) with histologically verified ductal pancreatic carcinoma. At the time when the patients were enrolled nine patients had lymph node metastases (stage III), and in 7 patients distant metastases (stage IV) were present. Mistletoe was administered twice a week by subcutaneous injection in a dosage of 1 ng per kg body weight. Monthly follow-ups included clinical status, multidimensional evaluation of quality of life, contrast enhanced computed axial tomography scan (CT scan) or ultrasonography, and determination of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Apart from one anaphylactic reaction, which necessitated suspension of treatment for a few days, no severe side effects were observed. No partial or complete remission was seen. Eight patients (50%) showed a CT-verified status of 'no change' according to World Health Organization criteria for at least 8 weeks. Median survival time in all patients was 5.6 months (range 1.5 to 26.5 months). Analysis of multidimensional evaluation of quality of life showed a stable course of disease in 7 patients. All except two patients claimed that mistletoe had a positive effect on their quality of life, with an obvious decline only during the last weeks of life. These results indicate that mistletoe is not able to significantly influence tumor growth in advanced pancreatic carcinomas. However, mistletoe treatment can stabilize quality of life, and therefore may help patients to maintain adequate life quality in their few remaining months.
Article
Previously, a strong stimulatory response of peripheral blood mononuclear cells (PBMC) to a fermented mistletoe extract (Iscador Pini, i.p.) could be observed in normal and allergic individuals. Aim of this study was therefore to analyse the cell subtypes involved in this in vitro reactivity. PBMC from 11 non-mistletoe treated healthy and allergic individuals were therefore investigated. Flow cytometric analyses revealed that this mistletoe extract stimulated T-cells (CD3+), especially T-helper cells (CD4+), as well as monocytes at concentrations of 100 or 1,000 micrograms/ml. Furthermore, an increased proportion of T- and T-helper cells expressing the interleukin-2 (IL-2) receptor (CD25) and monocytes expressing HLA-DR molecules, respectively, could be demonstrated. There was no evidence for a major involvement of B- (CD19+), natural killer- (NK-; CD56+) and T-suppressor cells/cytotoxic T-lymphocytes (CD8+). To get more insights whether the T-cell proliferation induced by i.p. was the consequence of a primary or a secondary type of immune response, kinetic studies (n = 5) were performed hereby comparing the reactivity of the non-recall antigen keyhole limpet hemocyanin (KLH) as well as the recall antigen purified protein derivative (PPD) derived from Mycobacterium tuberculosis with that of i.p. I.p. at a concentration of 100 micrograms/ml always exhibited the kinetics of a primary immune reaction. These findings were further substantiated by additional flow cytometric studies analysing changes in the proportions of naive (CD45RA+) and memory/effector cells (CD45RO+) during the exposure to i.p. It could be shown that the proportion of naive cells decreased and that of the transition stage increased, which could indicate that there was a change towards memory/effector cells. In conclusion, these data demonstrate that i.p.-related antigens act like "non-recall"-antigens, and the in vitro immune response involves T-cells as well as monocytes.
Article
Mistletoe extracts are used in adjuvant cancer treatment, but little is known concerning their mode of action. There is, however, evidence that antigens in these extracts may stimulate cells of the immune system, thereby modifying the altered immunological reactivity in tumour patients. In order to find out whether the postulated immunomodulatory properties of mistletoe extracts are mediated by cytokines, a spectrum of different cytokines was analysed in the supernatants of peripheral blood mononuclear cells (PBMC) from healthy (n = 23) and allergic (n = 16) individuals after stimulation with the fermented mistletoe lectin-1 (ML-1) free mistletoe extract Iscador Pini (IP) in vitro, and their cytokine patterns were compared to those from tumour patients with either breast cancer (n = 20) or colorectal tumours (n = 22). PBMC from healthy and allergic individuals produced high levels of TNF-alpha and IL-6 and to a lesser extent Th1- and Th2-related cytokines. This finding was in contrast to data obtained in tumour patients. Thus, the concentration of TNF-alpha was significantly lower in the cell cultures from breast cancer patients than in controls, and patients with colorectal tumours released IFN-gamma/IL-2 (5%) in the supernatants significantly less frequently than PBMC from healthy controls (26%). Similar results were obtained when the Th1- and monocyte/macrophage-related cytokines were analysed in the unstimulated cell cultures. These in vitro studies provide evidence that there is a reduced immunological reactivity to the fermented ML-1 free mistletoe extract in tumour patients and may give some clues as to how mistletoe-derived antigens could act on immune cells involved in the tumour defence.
Article
The three mistletoe (Viscum album L.) lectins. ML I, ML II and ML III, were tested on their ability to enhance the secretion of the cytokines tumor necrosis factor (TNF)alpha, interleukin (IL)-1 alpha, IL-1 beta and IL-6 by human monocytes obtained from healthy donors. At lectin concentrations from 0.02 to 20/pg ml (100-10,000-fold lower than those showing toxic effects), stimulations of cytokine production several-fold over control values were observed. The immunoactivating concentrations by the three lectins were found different for each donor. At toxic concentrations, the amounts of IL-1 alpha, IL-1 beta and to a less extent of TNF alpha in monocytes supernatants were particularly high. The data are discussed in relationship with the cytotoxic and immunoactivating effects of mistletoe lectins and their interest in cancer treatment.
Article
Mistletoe (Viscum album) extracts are widely used in adjuvant cancer therapy. We have investigated the in vitro responsiveness of T cells from mistletoe-treated cancer patients and untreated healthy donors to various preparations of mistletoe extracts. Proliferation of peripheral blood mononuclear cells from treated but not from untreated patients was observed in response to therapeutically used mistletoe extracts prepared from apple (mali) or pine (pini) host trees. The strongest proliferation was induced by a vesicle preparation of mali extract. Activation was strongly inhibited by interleukin-10. Using a newly developed flow-cytometry assay, we determined that cell growth was restricted to CD4 T cells. Analysis with a panel of monoclonal antibodies against the variable region of the T cell receptor beta chain (V beta) revealed an oligoclonal pattern of CD4 T cell activation. These results indicate that therapeutic administration of mistletoe extracts sensitizes a restricted set of CD4 T lymphocytes in mistletoe-treated patients.
Article
During the last 20 years, mutual communications between the immune, the endocrine and the nervous systems have been defined on the basis of physiological, cellular, and molecular data. Nevertheless, a major problem in the new discipline "Psychoneuroimmunology" is that controversial data and differences in the interpretation of the results make it difficult to obtain a comprehensive overview of the implications of immunoneuroendocrine interactions in the maintenance of physiological homeostasis, as well as in the initiation and the course of pathological conditions within these systems. In this article, we will first discuss the afferent pathways by which immune cells may affect CNS functions and, conversely, how neural tissues can influence the peripheral immune response. We will then review recent data, which emphasize the (patho)physiological roles of hippocampal-amygdala structures and the nucleus accumbens in neuroimmunomodulation. Neuronal activity within the hippocampal formation, the amygdaloid body, and the ventral parts of the basal ganglia has been examined most thoroughly in studies on neuroendocrine, autonomic and cognitive functions, or at the level of emotional and psychomotor behaviors. The interplay of these limbic structures with components of the immune system and vice versa, however, is still less defined. We will attempt to review and discuss this area of research taking into account recent evidences for neuroendocrine immunoregulation via limbic neuronal systems, as well as the influence of cytokines on synaptic transmission, neuronal growth and survival in these brain regions. Finally, the role of limbic structures in stress responses and conditioning of immune reactivity will be commented. Based on these data, we propose new directions of future research.
Article
Mistletoe extracts have been shown to exert immunomodulatory properties. However, little is known about changes in different immunological parameters during therapy. Aim of our study was, therefore, to investigate the influence of subcutaneous treatment in 8 volunteers who were exposed to an aqueous mistletoe extract (Viscum album Mali; VM) for 8 weeks. During in vivo exposure, VM induced the production of anti-ML-1 antibodies of the IgG-type. A pronounced proliferation of peripheral blood mononuclear cells (PBMC) could be observed in 6 volunteers. However, the activity and time of maximal response varied from one individual to the other. There was no correlation between the cellular and the humoral reactivity and different antigens present in this mistletoe extract may be operative at different levels of the immune system. In order to define more precisely the type of immune response, cytokines were measured in the supernatants of VM-stimulated cell cultures. VM induced the secretion of Th1- (IFN-gamma) or Th2- (IL-4) related cytokines and also the release of TNF-alpha and IL-6. All these different immunological phenomena can be best explained by presentation of mistletoe-related antigens to T- and B-cells via antigen presenting cells in the draining lymph nodes.
Article
Thionins are small basic peptides found in different plant species, which are known to exert cytotoxic properties. In addition, previous data indicated an activation of human granulocytes by thionins from European mistletoe (viscotoxins, VT). To extend these latter findings, we investigated the influence of VT and from thionins from wheat flour (purothionin) on human granulocytes by flow cytometry and tried to characterise the involved molecular structures and mechanisms. Phagocytosis was determined by incorporation of FITC-labelled Escherichia coli and respiratory burst by oxidation of dihydrorhodamine 123 to rhodamine 123. VT and purothionin significantly enhanced E. coli-stimulated phagocytosis and respiratory burst at 25 and 250 mu g/ml. Phagocytosis of damaged lymphocytes by granulocytes was detected by electron microscopy in the VT-stimulated (100 mu g/ml) but not in the control cultures. The poly-cationic structure of the intact ed by comparison of the burst and phagocytosis-enhancing effects induced by other poly-cationic (protamine sulphate, histone, poly-L-arginine, poly-L-lysine) and poly-anionic (poly-L-glutamic acid) peptides, while pore forming due to amphipathic properties seems to be less important. Ca2+ and Mg2+ could not inhibit VT-enhanced phagocytosis and, thus, could not inhibit binding of VT to granulocytes. In addition, verapamil at low concentrations inhibited VT activity, suggesting the involvement of Ca2+ channels for granulocyte activation by the VT. Similarly, thionins and histones in contrast to protamine sulphate induced cell death of granulocytes at 250 mu g/ml as demonstrated by an enhanced release of reactive oxygen intermediates in unstimulated granulocytes. From these data one may suggest that activity of VT is induced by strong unspecific ionic binding, probably followed by specific receptor binding, and thionins exhibit stimulatory and cytotoxic effects on immune cells, which have to be further characterised.
Article
Iscador, an aqueous extract of Viscum album L., has been widely used as an anti-cancer drug for several decades. Mistletoe lectins have the capacity to activate nonspecific defense mechanisms, and lectin-carbohydrate interactions may be involved in clinically applicable immunomodulation. During treatment with whole-plant mistletoe extract, an inflammatory reaction usually occurs at the site of the injection, early in therapy. These injection sites were examined histologically. Seven subjects received three subcutaneous injections of Iscador QuFrF or Iscador Qu Spezial (twice 0.1 mg and once 2.5 mg) during 9 days. In all subjects, examination of skin biopsies showed a normal epidermis. The dermal and subcutaneous regions contained a dense perivascular lymphocyte infiltrate and increased monocytes. We could not document any increase of plasma cells, eosinophils, mast cells, neutrophils, or granulocytes, as would be the case for a granulomatous infiltrate. In the blood, we observed a significant increase in neutrophils and monocytes 24 hours after administration of 2.5 mg of Iscador.
Article
Drugs, which are effective are also bond to exert adverse effects. This is also true for mistletoe extracts. Extracts from European mistletoe (Viscum album, VAL) belong to the complementary therapeutic regimens and are used for adjuvant cancer therapy. This study was performed to characterise immunological reactivity of patients with adverse effects during treatment with an aqueous VAL extract (Helixor). VAL-stimulated proliferation and cytokine release of peripheral blood mononuclear cells (PBMC) and anti-mistletoe lectin (ML)-1 antibody production were investigated. 34 patients with proven adverse effects due to VAL therapy (group 1) and 9 patients with unproven relation (group 2) were studied and compared to 14 tumour patients treated with VAL for more than 2 years without side effects (TTP). VAL-stimulated proliferation of PBMC of group 1 was significantly enhanced as compared to group 2 patients and TTP. PBMC from patients with local manifestations proliferated significantly stronger than those from patients with systemic symptoms. Anti-ML-1 antibodies of the IgE type were produced in patients with proven adverse effects but not in patients without adverse effects. Production of Th1 and Th2 specific cytokines varied considerably, indicating that different mechanisms were involved in the induction of adverse effects. In conclusion, our study provide evidence that adverse effects towards VAL (Helixor) are seldom and are dominated by an application site reaction suggesting the involvement of delayed type hypersensitivity (DTH) reactions.
European mistletoe (Viscum album L) has been used parenterally for more than 80 years as an anticancer medication with significant immunomodulating action. Since 1984, clinical experience with a Viscum album extract (Viscum album Quercus Frischsaft [Qu FrF]) among HIV-positive patients has suggested that it inhibits HIV disease progression. To determine the toxicity profile and biochemical effects of a Viscum album extract. A dose-escalating phase I/II study. 32 HIV-positive and 9 healthy participants. Standardized for its lectin and viscotoxin content, the extract was administered subcutaneously twice weekly in gradually increasing doses for 2 to 17 weeks per dose increase. Doses of 0.01 mg to 10.0 mg were administered. Adverse events, hematology, and biochemistry. No severe side effects were found. During gradual dose escalation, more adverse events occurred at the lower dose range. The hazard rate of systemic adverse events was highest among HIV-positive patients. Drug-related adverse events were flu-like symptoms and transient exacerbations of gingivitis, fever, and eosinophilia. An increase of serum urea nitrogen and serum creatinine levels occurred, as did a slight decrease in total protein caused by a minor fall in albumin concentrations. Dose dependence was apparent for inflammation and fever, which may or may not have been side effects of the preparation. Viscum album Qu FrF can be administered safely to HIV-positive patients. It induces immunomodulation in HIV-positive and healthy individuals and may inhibit the progression of HIV disease.
Article
An acidic arabinogalactan from European mistletoe (Viscum album L, VAL; 1.34 x 10(6) Dalton) was studied in detail because its immunological properties are poorly characterised. Flow cytometric studies focussed on PS-activated proliferation of human lymphocytes measured via incorporation of bromo-deoxyuridine (BrdU), granulocyte phagocytosis via ingestion of FITC-labelled E.coli, and respiratory burst via oxidation of dihydrorhodamine 123 to rhodamine 123. Cytokines were detected in the cell culture supernatants by ELISA. PS, in contrast to mistletoe lectins (ML), significantly stimulated proliferation of CD4+ T-cells but not CD8+ and CD19+ cells. However, ML influenced PS-mediated stimulation, with a synergistic effect in one and an inhibitory effect in another individual. Furthermore, IFN-gamma release was significantly enhanced by PS, favouring a T-helper cell type-1 cytokine pattern, further IL-6 was significantly stimulated, while granulocyte activity was not affected. VAL-PS exert yet unknown stimulatory activities, especially on specific CD4+ T-cells which may be influenced by other extract components like the ML. These components may contribute to the anti-tumour effect of VAL.
Article
Polysaccharide aus frischem Viscum album L.-Beerenextrakt und ihre Interaktion mit Viscum album-Agglutinin I In den dargestellten Untersuchungen wurden Frischpflanzenpreßsäfte aus Beeren von Viscum album L. hinsichtlich des Vorkommens und der Struktur der polymeren Kohlenhydrate untersucht. Aus lektin-, tannin- und proteinfreien Mikrofiltraten wurde ein Rohschleim isoliert, der mittels Anionenaustauschchromatographie in eine neutrale Fraktion (durchschnittliches Molekulargewicht 30 und 7 kDa) und drei saure Fraktionen (durchschnittliche Molekulargewichte etwa 1300 kDa) aufgetrennt wurde. Qualitative und quantitative Bestimmung der Zukkermonomeren sowie Bindungsstudien mittels Methylierungsanalytik ergaben für die sauren Fraktionen II bis IV das Vorliegen von sauren Arabinogalactanen mit einem Rhamnose-Galakturonsäure-Grundgerüst und hochverzweigten Arabinose-Galaktose-Seitenketten. Die Neutralfraktion setzte sich aus einem neutralen Arabinogalaktan neben geringeren Anteilen (etwa 10%) eines niedrig substituierten Xyloglucans zusammen. Untersuchungen zur Interaktion der 1340 kDa Arabinogalaktane II und III mit Viscum album-Agglutinin I (VAA I) ergaben deutliche Wechselwirkungen im Sinne einer gegenseitigen Bindung. Polysaccharide der Fraktion II zeigten nur schwach ausgeprägte Interaktionen, während die neutralen Polymere aus Fraktion I keine Bindung mit VAA I eingingen. Analoge Interaktionen des Polysaccharides III mit VAA I wurden zusätzlich in einem BIACORE-Assay detektiert. Im Hämagglutinationstest bewirkte Zusatz der vier Polysaccharid-Fraktionen eine leicht verstärkte Agglutination. Alle durchgeführten Untersuchungen belegen ausgeprägte Interaktionen zwischen VAA I und Mistelpolysacchariden.
Article
Unlabelled: A patient with inoperable adenocarcinoma of the pancreas was treated with intraperitumoral and peritumoral injections of a Viscum album L. extract containing 5,700 ng/mL mistletoe lectin, mainly mistletoe lectin 1 (Abnobaviscum Quercus 2) for 5 weeks (1 injection per week). After the third injection (day 22), a marked eosinophilia was observed (1,800 per microliter) that rose to 3,268 per microliter after the fifth injection (day 42). Furthermore, histology performed on day 28 revealed accumulation of eosinophils in ductal lesions and adjacent stroma in addition to the features of ductal adenocarcinoma. In order to investigate whether eosinophilia correlated with immunological features, we analyzed cytokine production of peripheral blood mononuclear cells (PBMC) from this patient after stimulation with antigens known to "unmask" an individual's predisposition for defined immunoreactions, namely purified protein derivative (PPD) as a stimulator of T-helper (TH1)1-cells and tetanus toxoid (TT) as an activator of TH2-cells. PBMC of the patient showed a strong proliferation and production of interleukin (IL)-5 and IL-10 after incubation with TT indicating a type-2 response. Simultaneously, PBMC were induced to proliferate and produce interferon gamma (IFN-gamma) by incubation with PPD suggesting also a type-1 response. These data would readily explain the eosinophilia because eosinophils are effector cells of type-2 reaction but also require type-1 cytokines. Although the overall clinical course of the patient was rapidly progressive, temporary stabilization of the patient's general condition during mistletoe treatment was observed. It is, however, still an open question whether this transient benefit was due to the induction of eosinophilia by a type-2 response. Conclusion: Before high-dose intratumoral and peritumoral treatment with a Viscum album L. extract containing mistletoe, lectin 1 can be associated with hypereosinophilia and strong production of TH1 as TH2 cytokines as well.
Article
A dysregulation between cellular immunity (Th1 cells) and humoral immunity (Th2 cells) is a characteristic of cancerous diseases. Viscum album (VA) extract has an immunomodulatory effect and can be used in the treatment of cancer patients, either following or in combination with chemo- /radiotherapy. In this pilot study, we investigated the effect of VA extract on the serum levels and production of cytokines in a group of cancer patients undergoing treatment (N = 16) in comparison with healthy untreated controls (N = 11). The serum levels of interleukin-12 (IL-12) (p40 and p70), and the production of gamma interferon (IFN-gamma), interleukin 2 (IL-2), and interleukin-4 (IL-4) in peripheral blood mononuclear cells (PBMC) were measured in patients before treatment and on days 3, 5, 8, 15, and 21-29 during therapy, and in the control group at the same time intervals over a two-week period. Cytokine levels were determined by ELISA. In cancer patients, the serum levels of IL-12 (p40 and p70) before therapy were about 3-fold higher than in controls. They increased during therapy, with a borderline significance (Wilcoxon paired signed-rank test, P = 0.06). In PBMC the production of IFN-gamma and IL-2 (before therapy respectively 3-fold and 9-fold lower than in controls) increased significantly (Wilcoxon paired signed-rank test and Mann-Whitney U-test, P < 0.05) during treatment. In PBMC, IL-4 production was in the same range as in controls, and remained unaltered during therapy. In conclusion, the results of this study show that treatment with VA extract leads an increase in Th1 cytokine levels (IFN-gamma and IL-2), which suggests that cell-mediated immunity could be positively affected.
Article
Mistletoe lectin is thought to constitute the active principle in extract preparations from mistletoe, which are widely used as immunomodulators in adjuvant tumor therapy. However, no study exists which compares the immunological potency of different well-defined mistletoe lectin preparations on human immune cells. Therefore, in the present study the biological effects of an aqueous mistletoe extract, standardized for mistletoe lectin I (eML), the isolated natural mistletoe lectin (nML), and the recombinant form of this lectin (rML) on human peripheral blood monocytes and lymphocytes were compared with respect to cell viability and cytokine induction. After 48-hr incubation of peripheral blood mononuclear cells (PBMC) with rML, nML, and eML, a continuous concentration-dependent decrease in cell viability was found with an IC50 of about 3 ng/ml for rML and nML and 10 ng/ml for eML, respectively. This effect also was seen when isolated lymphocytes and monocytes were separately incubated with the lectin preparations. After incubation of PBMC and isolated monocytes of 5/10 blood donors with eML, an increase in cell viability was found at lectin concentrations between 10 and 1,000 pg/ml. This effect was not seen with the pure lectin preparations nML and rML. After 48-hr incubation of PBMC with rML, nML, and eML, induction of IL-1-beta, TNF-alpha, IL-2, IL-6, and IL-10 but not IFN-gamma was measured. For IL-1-beta it could be shown that cytokine induction took place at a broad lectin concentration range (0.1-100 ng/ml). Cytokine levels varied greatly in the PBMC cultures of the different blood donors. When monocytes were separately incubated with eML, nML, and rML for 48 hr, high levels of IL-1-beta were found. In contrast, in cultures of separated lymphocytes from the same donors only a minimal production of IL-1-beta and no production of IFN-gamma was found after incubation with rML, nML, and eML. It is concluded that there are quantitative differences in the immunomodulatory effects of the mistletoe lectin preparations on human monocytes and lymphocytes. Therefore, measurement of cell viability and cytokine induction may be a diagnostic laboratory tool to determine the immunological potency of various mistletoe preparations and may help to clarify the clinical benefit of therapies with these substances.
Article
We examined the immunomodulatory properties of the mistletoe preparation Lektinol (standardized for mistletoe lectin-1) and recombinant mistletoe lectin-1 (rML-1) in vitro by assessing alterations in the cytokine response of human whole blood. Lektinol or rML-1 alone did not induce any cytokine release in unstimulated whole blood. However, the lipopolysaccharide (LPS)-induced release of tumor necrosis factor (TNF)-alpha was increased, and the secretion of interleukin (IL)-10 was reduced by Lektinol at a mistletoe lectin-1 (ML-1) concentration of 0.5 to 5 ng/ml, whereas the LPS-induced secretion of IL-1 beta, IL-6, IL-12, and interferon-gamma was not affected. Lektinol did not alter the initial phase of TNF-alpha production but sustained TNF-alpha levels longer than in the LPS controls. Recombinant ML-1, but not the recombinant B-chain alone, also increased TNF-alpha release and decreased IL-10 release. We propose that the increase in TNF-alpha release is due to a specific inhibition of IL-10 release by Lektinol. This conclusion is based on the observation that blocking of endogenously formed IL-10 by a neutralizing antibody results in a similar increase of TNF-alpha in the late production phase after LPS stimulation. This hypothesis was also corroborated by the finding that when endogenously formed IL-10 was blocked, Lektinol could no longer increase TNF-alpha release. These results indicate that Lektinol modulates the cytokine response of human whole blood to LPS in a proinflammatory fashion, which can be attributed to ML-1.
Article
IL-17 is a cytokine that has been reported to be produced by T lymphocytes. In vitro, IL-17 activates fibro-blasts and macrophages for the secretion of GM-CSF, TNF-alpha, IL-1beta, and IL-6. A number of these cytokines are involved in the airway remodeling that is observed within the lungs of asthmatic individuals. In this study, we investigated the expression of IL-17 in sputum and bronchoalveolar lavage specimens obtained from asthmatic subjects and from nonasthmatic control subjects. IL-17 was detected through use of immunocytochemistry, in situ hybridization, and Western blot. Bronchial fibroblasts were stimulated with IL-17, and cytokine production and chemokine production were detected through use of ELISA and RT-PCR. Using immunocytochemistry, we demonstrated that the numbers of cells positive for IL-17 are significantly increased in sputum and bronchoalveolar lavage fluids of subjects with asthma in comparison with control subjects (P <.001 and P <.005, respectively). We demonstrated that in addition to T cells, eosinophils in sputum and bronchoalveolar lavage fluids expressed IL-17. Peripheral blood eosinophils were also positive for IL-17, and the level of IL-17 in eosinophils purified from peripheral blood was significantly higher in subjects with asthma than in controls (P <.01). To further investigate the mechanism of action of IL-17 in vivo, we examined the effect of this cytokine on fibroblasts isolated from bronchial biopsies of asthmatic and nonasthmatic subjects. IL-17 did enhance the production of pro-fibrotic cytokines (IL-6 and IL-11) by fibroblasts, and this was inhibited by dexamethasone. Similarly, IL-17 increased the level of other fibroblast-derived inflammatory mediators, such as the alpha-chemokines, IL-8, and growth-related oncogene-alpha. Our results, which demonstrate for the first time that eosinophils are a potential source of IL-17 within asthmatic airways, suggest that IL-17 might have the potential to amplify inflammatory responses through the release of proinflammatory mediators such as alpha-chemokines.
Article
Despite advances in the therapy of chronic hepatitis C for some hepatitis C virus (HCV) genotypes interferon and ribavirin combination therapy is effective in less than 50% of patients. Abnobaviscum Quercus (AQ) is a mistletoe preparation containing defined amounts of mistletoe lectins (ML). It has shown immunomodulatory properties in vitro and in vivo. In small clinical trials AQ resulted, within an anthroposophical treatment concept, in a biochemical or virological response in up to 40% of patients with chronic hepatitis C. In order to evaluate the effect of this preparation we conducted an individually controlled cohort study. 25 patients with chronic hepatitis C (mean duration 147 +/- 80 months) and elevated alanine aminotransferase (ALT) levels were included in the study. As control they were observed for 6 months pre-treatment. This pre-treatment period was followed by 6 months of active treatment in which the mistletoe preparation was subcutaneously injected three times a week. Main outcome parameters were normalization of ALT and viral load. Hepatitis C associated signs and symptoms like tiredness, fullness in the right upper abdomen and musculoskeletal pain were assessed monthly in a standardized questionnaire. All 25 patients completed the study and most of the patients wanted to continue treatment. Mean duration of treatment was 9.1 months. None of the patients had complete or partial normalization of ALT or HCV RNA levels during pre-treatment or treatment period. Mean ALT did not change during the study. Tiredness, fullness in the right upper abdomen and musculoskeletal pain were present in 18, 8 and 4 patients respectively. They significantly improved within two months of treatment. A significant eosinophilia (p=0.0001) occurred between month 2 and 6 during treatment. 9 month treatment with a ML containing mistletoe preparation has no effect on viral load or ALT as markers of activity in patients with chronic hepatitis C. However, frequency and intensity of clinical signs and symptoms in our patients decreased significantly, similar to reports of improved quality of life in tumour patients treated with such preparations. A significant eosinophilia suggests that ML containing mistletoe preparations induce a T-helper 2 immune response.
Article
In recent years, there has been an increasing appreciation of the important contribution of bone-marrow-related, hemopoietic mechanisms to allergic diseases. Eosinophil/basophil-progenitor levels fluctuate in the peripheral blood during allergen exposure and the cells home to peripheral tissue, where they differentiate. It is becoming apparent that several cytokines, particularly IL-5, have multiple effects on progenitors and allergic inflammation. Within the past few years, studies of the therapeutic implications of this bone marrow contribution to atopy have been initiated; the effects of corticosteroids, leukotriene-receptor blockers, antagonism of IL-5 and modulation of differentiation by retinoic acid on progenitors will be reviewed.
Article
The plant lectin Viscum album agglutinin-I (VAA-I) and the interleukin-15 (IL-15) cytokine are two molecules with potential therapeutic properties known to modulate neutrophil functions when used separately. This study was conducted in order to better understand the mode of action of VAA-I and to elucidate how VAA-I could modulate IL-15-induced neutrophil responses. We found that VAA-I cannot induce phosphorylation events in human neutrophils. However, it enhances phagocytosis by itself without altering IL-15-induced phagocytosis. VAA-I was found to reverse the ability of IL-15 to delay neutrophil apoptosis and this was correlated with an inhibition of IL-15-induced de novo protein synthesis. In addition, we also found that IL-15 cannot reverse or attenuate the caspase-induced gelsolin fragmentation observed during apoptosis as assessed by immunoblotting. We conclude that VAA-I can be used to modulate some, but not all, IL-15-induced neutrophil responses and that it acts independent of phosphorylation events.
Article
Mistletoe (Viscum album) is a plant that is semiparasitic of several trees: apple, oak, pine trees, etc. Because of the probable cytolytic action of one of the leaf's most abundant composites, in some countries mistletoe is used as a complementary medicine. Although only a few adverse reactions have been noted (cephalea, fever), cases of anaphylactic shock have been described. We present three cases of severe reaction after injection of mistletoe extract. Two of the patients had cancer. The third, whose brother had cancer, used the plant for preventive purposes. We discuss the danger of possible severe reactions due to the use of products employed in so-called alternative therapies.
Article
After administering standardized mistletoe extract, Viscum album L, (Iscador injections of 0.1 mg twice and 1.0 mg in defined intervals) the functional characteristics of microcirculation and immunological behavior of the white blood cells in different target tissues (derma, intestine) were investigated in healthy volunteers by vital microscopic investigation over 13 days of observation. The investigations showed a temporarily improved function of the microcirculation and an increased adhesion and transmigration of white blood cells in the target tissue areas. This observation was evaluated as a biologically relevant immunomodulation. Further investigations under pathophysiological conditions with regard to complementary administration of the test substance (e.g. to cancer patients) appear promising.
Article
Several studies have been performed in tumour patients to analyse the immunological response to mistletoe extracts. Considering the fact that these extracts are given subcutaneously in most instances, the kind of application resembles a typical immunization schedule. We therefore wanted to see how those extracts act on immunocompetent cells of healthy individuals hoping that this kind of provocation test may give new informations about a more specific application of these extracts in certain diseases. 47 healthy individuals were exposed for twelve weeks either to Iscador Quercus special (IQ) known to be rich in mistletoe lectin (ML)-1 (n = 16), to Iscador Pini (IP) being poor in ML-1 but enriched in viscotoxins (n = 15), or to placebo (physiological saline) (n = 16) in a randomised, double-blinded placebo-controlled study. Humoral immunoreactivity was analysed by measuring antibodies towards the two compounds ML-1 and viscotoxin VA2 (VA2). Sera were collected in intervals of four weeks up to week 12 and again three months after last exposure. None of the subjects had antibodies to ML-1 or VA2 before exposure. In week 12, anti-ML-1 antibodies of the IgG-type were found in all 16 IQ-treated individuals but only 6 of the 15 probands exposed to IP. In contrast, anti-VA2 IgG-antibodies could be detected in all individuals of both groups. The antibodies were preferentially of the IgG1 and IgG3 type while antibodies of the IgA and IgM type were produced only in a few probands. Antibodies of the IgE-type occurred only in the IQ-exposed individuals and were directed against ML-1 but not VA2. None of the probands receiving placebo developed antibodies to ML-1 or VA2. Severe side effects were not observed in any of the probands. These data obtained in healthy individuals clearly indicate that IQ and IP-extracts can induce antigen-specific humoral responses. They may, therefore, provide, a solid basic for the evaluation of the humoral immune response in disease states.
Article
Mistletoe extracts exert immunomodulatory properties on immunocompetent cells of the innate as well as the specific immune system. These effects have been mainly ascribed to mistletoe lectin 1 (ML-1) present in most of the extracts. However, it became evident that also other components of these extracts may induce immunological reactions, and especially viscotoxins (VT) may be of relevance. Aim of the study was, therefore, to evaluate whether VT like ML-1 could activate B-cells and lead to the production of VT-specific antibodies. Sera from 26 patients with different tumours who were treated with the mistletoe extract ABNOBAviscum Mali (AM) 4 for at least 18 weeks were analysed before therapy and after 3, 6, 9, 12, and 18 weeks. Sera were tested by ELISA against the four viscotoxins A1, A2, A3, B, as well as against ML-1. Within the observation period twenty-four (92%) of the 26 patients developed antibodies to at least one of the four VT and 25 (96%) to ML-1. In most instances, anti-VT antibodies appeared after 6-9 weeks of treatment. The antibodies were predominantly of the IgG type belonging preferentially to the IgG1 and IgG3 subclass. IgE antibodies were found only to VT-B and to ML-1. There was no relation between the development of antibodies to VT and ML-1, and also cross-reactivity could be excluded with high probability. These data indicate that not only ML-1 but also VT induce immunological responses in patients treated with mistletoe extracts. Whether there is any relationship to the postulated anti-tumour effect of mistletoe extracts has, however, still to be evaluated.
Article
The mucosal adjuvant properties of the three type 2 ribosome-inactivating proteins (RIPs) from the European mistletoe, Viscum album L., were investigated. Mistletoe lectins were compared with cholera toxin (CT) as adjuvants when delivered nasotracheally together with herpes simplex virus glycoprotein D2 (gD2). All three mistletoe lectins (MLI, MLII, MLIII) were potent mucosal adjuvants. Co-administration of MLI, MLII or MLIII with gD2 led to significantly higher levels of gD2-specific mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) antibody than when the antigen was delivered alone. The levels of antibodies induced were similar to those generated in mice immunized with gD2 and the potent mucosal adjuvant CT. Administration of ML1 with gD2 enhanced the antigen-specific splenic T-cell proliferative response. Interleukin-5 (IL-5), but not interferon-gamma (IFN-gamma), was detected in supernatants from splenocytes stimulated in vitro with gD2. This indicates that MLI enhanced type 2 T-helper cell (Th2) responses to the bystander antigen, gD2. Analysis of the gD2- and lectin-specific IgG subclass titres in mice immunized with gD2 and MLI, MLII or MLIII revealed a high ratio of IgG1 : IgG2a, which is compatible with the selective induction of Th2-type immune responses.
Article
Accumulating evidence indicates that T cell-mediated dominant control of self-reactive T cells contributes to the maintenance of immunologic self-tolerance and its alternation may lead to development of autoimmune disease. Efforts to delineate such a regulatory T cell population have revealed that CD25+ cells within the CD4+ population in normal naive animals including humans possess the regulatory activity. The CD25+CD4+ regulatory T cells are produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling various immune reactions.
Article
Recent evidence suggests that the placebo effect is mediated by the dopaminergic reward mechanisms in the human brain and that it is related to the expectation of clinical benefit. On the basis of this theory, we propose some criteria for the proper investigation of the placebo effect, and review the evidence for a placebo effect in Parkinson's disease, depression, pain, and other neurological disorders. We also discuss the evidence for the use of placebos in long-term substitution programmes for the treatment of drug addiction.
Article
In this study we performed several methods for the determination of cytokines (RT-PCR for the demonstration of cytokine mRNA and flow cytometry for the analysis of intracellular cytokines) and compared them with a recently established test system stimulating peripheral blood mononuclear cells (PBMC) with TH1- and TH2-relevant recall antigens and analysing type 1 and type 2 cytokines by ELISA. Aim of the study was therefore to evaluate the reliability of TH1/TH2 cytokine profiles in two individuals with different types of an allergic/atopic disposition: one of them showed a strong TH1/type 1-mediated tuberculin-reaction (subject A), the other (subject B) revealed elevated IgE-levels and eosinophil counts (TH2/type 2-mediated). PBMC were incubated with the type 1-antigen purified protein derivative (PPD) and the type 2-antigen tetanus-toxoid (TT) for seven days. From the comparison of ELISA with RT-PCR and flow cytometry-analysis it became evident that all three methods allowed the definition of subject A as a 'type 1-responder'. Subject B showed a pure type 2-response in the ELISA method; PCR and flow cytometry analysis revealed the simultaneous production of type 1- and type 2-cytokines resulting in a mixed type 1/type 2-profile. Active immunization of subject A with TT at the end of the observation period of 12 months resulted in a transient shift from type 1- to a mixed type 1/type 2-profile (simultaneous PPD-induced IFN-gamma- and TT-induced IL-5 production). From this pilot study based on clear cut clinical criteria concerning either a humoral or cellular immunological reactivity towards allergens/antigens it is suggested that the determination of type 1/type 2-cytokines by ELISA in supernatants of PBMC stimulated with type 1/type 2-relevant antigens is a useful approach for a better classification of 'type1-' or 'type 2-responder'.
Article
Active specific immunotherapy holds great potential in the search for new therapeutic approaches for patients with cancer. Much preclinical and clinical evidence has shown that the immune system can be polarised against malignant cells by several vaccination strategies. Although no anticancer vaccine can be recommended outside clinical trials at present, tumour response and immunological findings in animals and humans should prompt researchers to investigate further the potential of this biotherapy. We summarise strategies for cancer vaccines so far implemented in the clinical setting, report the results of more than 200 clinical trials published over the past two decades, and discuss insights into preclinical tumour immunology that might aid the design of the next generation of cancer vaccines.
Article
The search for new therapeutic approaches to haematological malignant disease involves exploitation of the antitumour potential of adaptive immunity-the most specific killing system against cancer currently known. Here, we summarise immunological strategies behind active specific immunotherapy, and describe the clinical and immunological results from trials published to date. Available data in humans support the hypothesis that various vaccination regimens can polarise adaptive immunity towards effective control of cancer-cell growth. However, the exploratory nature of clinical studies done thus far does not allow any cancer vaccine to be used as standard treatment for haematological malignant disorders. Because the cause of disease recurrence is the presence of minimal residual disease after conventional treatments, the adjuvant setting might be the most appropriate therapeutic strategy for active specific immunotherapy, when the immunosuppressive effects of bulky disease are virtually absent and when the effector-target ratio is favourable. In the near future, completion of randomised phase III trials as well as clinical implementation of the most recent insights into tumour immunology that aim to overcome immune tolerance towards malignant cells should allow investigators to define the actual role of vaccines in the management of haematological tumours.
Article
Mistletoe preparations, which are widely used among patients with cancer in Germany, have immunomodulating properties in vitro and in vivo. The aim of this evaluation was to determine and compare the effects of a lectin-rich (Iscador Qu [IQ] special, Weleda Company, Schwäbisch, Gmünd, Germany.) and a lectin-poor but viscotoxin-rich (Iscador Pini [IP] Weleda Company) mistletoe preparation on clinical and hematologic parameters in healthy subjects. In a double-blinded study, 48 volunteers were randomized to one of three groups: 16 received IQ or IP in increasing doses or placebo twice per week subcutaneously for 12 weeks. The differential blood count and the acute phase markers haptoglobin and C-reactive protein were examined weekly and the symptoms were scored using standardized questionnaires. IQ resulted in significant eosinophilia (315 +/- 109) beginning at week 5 (until week 12) compared to IP (183 +/- 120) or placebo (200 +/- 179). Furthermore, the acute phase marker haptoglobin was significantly increased in the IQ group during week 4. Dose-dependent local reactions (LRs) at the injection site occurred in all subjects who received mistletoe preparations but were stronger in the IQ-treated subjects than in the IP-treated group. The LRs observed in the IQ-treated group were characterized by stronger itching and longer latency than LRs in the IP-treated group (p < 0.05). Severe side-effects did not occur in any of the probands. IQ but not IP can induce eosinophilia in healthy individuals, and this may be related to its content of mistletoe lectins. In contrast, exposure to the viscotoxin-enriched extract IP did not result in specific changes of hematologic parameters. Furthermore, intensity and time course of local reactions seemed to depend on the concentration of mistletoe lectins in those extracts.
Article
In this study, we analysed the recall antigen-induced cytokine production by peripheral blood mononuclear cells (PBMC) from 31 patients with multiple sclerosis (MS) with a relapsing-remitting (rr) and a relapsing-progressive (rp) course and from 40 healthy controls. Cells were stimulated with purified protein derivative (PPD; type 1 response) and tetanus toxoid (TT; type 2 response). Cytokines were determined in the supernatants by ELISA. One of the interesting findings was that healthy controls showed more frequently an IL-5 production after incubation with TT than MS-patients (68% vs.37%; p<0.01), while the type 1 reactivity was only slightly enhanced in MS patients as compared to the controls. However, within the MS patients, there was a significant difference in the incidence of the type 1 reactivity comparing patients with an rp and an rr course (60% vs. 24%; p<0.05). Furthermore, the frequency of a type 0 profile (simultaneous PPD-induced IFN-gamma and TT-induced IL-5 production) was fourfold higher in rr than in the rp patients (43% vs. 10%, p<0.05). In vitro analysis of cytokine profiles in MS could therefore be an interesting approach to evaluate the prognosis of MS (rr vs. rp) already at the beginning of the disease. Thus, it seems that the presence of a type 0 profile is a valid indicator for a favorable course, while a type 1 profile is rather associated with rp MS.