No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Manipulating IL-10 signalling blockade for better immunotherapy
... 9 The receptor structures of IL-10 family cytokines, the signaling pathways, the biological functions and applications for the treatment of cancers, and autoimmune diseases have been reviewed extensively. 1,[10][11][12][13][14][15][16][17] As for cancer therapy, targeting IL-10 has yet to achieve the similar clinical benefit obtained by the immune checkpoint inhibition therapy. Either blocking IL-10 or systemic administration of IL-10 inhibit tumor growth in animal models or clinical trials, reflecting the complexity and difficulty of targeting IL-10 for cancer therapy. ...
... 11 Vaccination with simultaneous IL-10 signaling blockade better inhibits tumor growth Immunization and simultaneously blocking IL-10 using IL-10 receptor monoclonal antibodies drastically increase vaccineinduced antigen-specific CD8 + T cell responses, regardless the immunogen is composed of virus-like particles, peptides, soluble antigens, or nucleotides (Table 1). 10,[18][19][20] The enhanced vaccineinduced T cell responses can also be achieved by using soluble IL-10 receptor, 21 peptide-based IL-10 receptor antagonist, 22,43 or oligonucleotides. 23 Subcutaneous administration of anti-IL-10 receptor antibodies together with a vaccine, instead of intraperitoneal injection of anti-IL-10 antibodies, also elicits stronger antigen-specific CD8 + T cell responses, yet at a much lower magnitude. ...
... Depletion of CD4 + T cells did not affect the PEG-IL-10-inflicted tumor control, while preventing migration of T cells to/from the tumor retained the rejection of tumors upon IL-10 treatment. 10 In a clinical trial, PEG-IL-10 was well tolerated and had an immunologic and clinical benefit in solid tumors, especially in renal cell carcinoma (RCC) and uveal melanoma. 29 PEG-IL-10 induces CD8 + T cell immunity in cancer patients, including elevation of interferon-γ and granzyme B, expansion and activation of intra-tumor CD8 + T cells, and proliferation and expansion of LAG-3+ PD-1+ CD8 + T cells. ...
Interleukin 10 (IL-10) belongs to IL-10 family cytokines that are critical for maintaining the integrity of epithelial tissues, protecting pathogenic infection, and preventing excessive immune responses to damage self. Temporal IL-10 signaling blockade enhances vaccine-induced tumor regression by CD8 + T cells. IL-10, especially pegylated IL-10, mediates tumor regression by expanding tumor-infiltrating CD8 + T cells. Moreover, targeting IL-10 enhances immune checkpoint inhibitor mediated tumor regression. In the current paper, we will review recent advances in this area and discuss the complexity of IL-10 manipulation for cancer therapy.
... The main function of IL-10 is to limit immune responses against foreign and self-antigens, to avoid excessive immune response damage to self, via inhibiting the function of professional antigen presenting cells [12]. Temporal blockade of IL-10 at the time of immunization drastically increases vaccine-induced CD8+ T cell responses [13,14]. This phenomenon can be observed when HPV VLPs, soluble antigen, peptide, or DNA are used as immunogens [14]. ...
... Temporal blockade of IL-10 at the time of immunization drastically increases vaccine-induced CD8+ T cell responses [13,14]. This phenomenon can be observed when HPV VLPs, soluble antigen, peptide, or DNA are used as immunogens [14]. Compared with vaccination using HPV16 long E7 peptide in incomplete Freund's adjuvant on its own, blocking IL-10 at the time of immunisation elicits significantly higher numbers of CD8+ T cells and attracts more CD4+ and CD8+ T cells to the tumour site [15,16]. ...
... Blocking IL-10 at the time of immunisation does not increase the survival time of TC-1 tumour bearing mice Previous studies show temporal blocking IL-10 at the time of immunisation drastically increases vaccine induced antigen specific CD8+ T cell numbers [14,25]. We wish to investigate whether blocking IL-10 at the time of immunisation, which increases the numbers of antigen specific IFNγ CD8+ T cells, better prevent TC-1 tumour growth in mice than immunisation without IL-10 signalling blockage, especially in therapeutic setting. ...
Background:
Therapeutic vaccines against cervical cancer remain ineffective. Previously, we demonstrated that blocking the signalling of a cytokine, interleukin 10, at the time of immunisation elicited significantly higher numbers of antigen specific T cells and inhibited tumour growth in mice.
Results:
In the current paper, we demonstrate, in a HPV16 E6/E7 transformed TC-1 tumour mouse model, that despite increased antigen specific T cell numbers, blocking IL-10 signalling at the time of immunisation does not increase the survival time of the TC-1 tumour bearing mice compared to mice receiving the same immunisation with no IL-10 signalling blockade. Moreover, the function of tumour infiltrating T cells isolated 3 weeks post TC-1 transplantation is more suppressed than those isolated 2 weeks after tumour inoculation. We demonstrate that synthesized caerin peptides, derived from amphibian skin secretions, 1) were able to inhibit TC-1 tumour growth both in vitro and in vivo; 2) are environmentally stable; and 3) promote the secretion of pro-inflammatory interlukine-6 by TC-1 cells. Notably caerin peptides were able to increase the survival time of TC-1 tumour bearing mice after therapeutic vaccination with a HPV16E7 peptide-based vaccine containing IL-10 inhibitor, via recruiting increased levels of T cells to the tumour site.
Conclusion:
Caerin peptides increase the efficacy of a therapeutic vaccine by recruiting more T cells to the tumour site.
... 2 IL-10 plays a central role in infection by limiting the immune response to pathogens and thereby preventing excessive damage to the host. 3 IL-10 can abort T cell responses when present during priming stage of an immune response and inhibit ongoing T cell activity to viral infections. 4 Also, IL-10 acts directly on T cells to limit proliferation, functional differentiation, and effector activity. ...
... Many attempts have been made to develop clinical grade anti-IL-10 anti-bodies, anti-IL-10 receptor antibodies, or IL-10 signaling inhibitors, using different techniques such as recombinant DNA technology, phage display and screening, and selection of short oligonucleotide aptamers. 3 However, these techniques are time consuming and labor intensive. ...
... Strong Th1 responses correlate with viral clearance and tumor rejection. 3 Using U937 cells as a model, Fig. 3 displays the IL-10 ELISA results of the IL-10 inhibition activity of the P1 modified peptides. Compared to the inhibitory activity of P1, it can be clearly seen that, at same concentration, C-terminal truncation reduced the inhibiting magnitude. ...
Interleukin 10 (IL-10) is a cytokine that is able to downregulate inflammation. Its overexpression is directly associated with the difficulty in the clearance of chronic viral infections, such as chronic hepatitis B, hepatitis C and HIV infection, and infection-related cancer. IL-10 signaling blockade has been proposed as a promising way of clearing chronic viral infection and preventing tumor growth in animal models. Recently, we have reported that peptides with a helical repeating pattern of hydrophobic and hydrophilic residues are able to inhibit IL-10 significantly both in vitro and in vivo (1) . In this work, we seek to further study the inhibiting mechanism of these peptides using sequence-modified peptides. As evidenced by both experimental and molecular dynamics simulation in concert the N-terminal hydrophobic peptide constructed with repeating hydrophobic and hydrophilic pattern of residues is more likely to inhibit IL10. In addition, the sequence length and the ability of protonation are also important for inhibition activity.
... HPV prophylactic vaccine introduced a decade ago effectively prevents HPV infection and may eradicate cervical cancer in countries that the vaccines are well distributed (McGregor et al., 2018). However, the vaccine is ineffective for those already infected with HPV and developing countries that have most cervical cancer patients have limited resources to vaccinate those at risk (Ni et al., 2015). Therefore, development of effective cervical cancer therapies remains as an urgent task. ...
... Cancer immunotherapy is becoming a routine cancer treatment option following the introduction of immune checkpoint antibodies (Diesendruck and Benhar, 2017). Therapeutic vaccines target cancer cells through activation or induction of antigen specific T cells, with minimal affection of normal cells and tissues (Ni et al., 2015). The efficacy of therapeutic vaccines is far from satisfactory in clinical trials, up to now, few vaccines such as synthetic long peptide (SLP) vaccines have shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained inclusive (Galliverti et al., 2018). ...
... The efficacy of therapeutic vaccines is far from satisfactory in clinical trials, up to now, few vaccines such as synthetic long peptide (SLP) vaccines have shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained inclusive (Galliverti et al., 2018). An ideal therapeutic vaccine should be able to elicit high quality and enough numbers of effective T cells, which can migrate to the tumor site, and overcome the tumor immunosuppressive microenvironment and kill the tumor cells via the process such as apoptosis (Ni et al., 2015). ...
... HPV prophylactic vaccine introduced a decade ago effectively prevents HPV infection and may eradicate cervical cancer in countries that the vaccines are well distributed (McGregor et al., 2018). However, the vaccine is ineffective for those already infected with HPV and developing countries that have most cervical cancer patients have limited resources to vaccinate those at risk (Ni et al., 2015). Therefore, development of effective cervical cancer therapies remains as an urgent task. ...
... Cancer immunotherapy is becoming a routine cancer treatment option following the introduction of immune checkpoint antibodies (Diesendruck and Benhar, 2017). Therapeutic vaccines target cancer cells through activation or induction of antigen specific T cells, with minimal affection of normal cells and tissues (Ni et al., 2015). The efficacy of therapeutic vaccines is far from satisfactory in clinical trials, up to now, few vaccines such as synthetic long peptide (SLP) vaccines have shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained inclusive (Galliverti et al., 2018). ...
... The efficacy of therapeutic vaccines is far from satisfactory in clinical trials, up to now, few vaccines such as synthetic long peptide (SLP) vaccines have shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained inclusive (Galliverti et al., 2018). An ideal therapeutic vaccine should be able to elicit high quality and enough numbers of effective T cells, which can migrate to the tumor site, and overcome the tumor immunosuppressive microenvironment and kill the tumor cells via the process such as apoptosis (Ni et al., 2015). ...
Host defense caerin 1.1 and 1.9 peptides, isolated from the glandular secretion of Australian tree frogs, the genus Litoria, have been previously shown to have multiple biological activities, including the inhibition of human papillomavirus (HPV) 16 early protein E7 transformed murine as well as human cancerous cell proliferation both in vitro and in vivo. However, the mechanism underlying their anti-proliferative activities against HPV18+ cervical cancer HeLa cells remains unknown. This study comparatively investigated the anti-proliferation on HeLa cells by caerin 1.1, 1.9, and their mixture, followed by confocal microscopy examination to assess the cellular intake of the peptides. Tandem mass tag labeling proteomics was employed to reveal the proteins that were significantly regulated by the peptide treatment in cells and cell growth environment, to elucidate the signaling pathways that were modulated. Western blot was performed to confirm the modulation of the pathways. Both caerin 1.1 and 1.9 highly inhibited HeLa cell proliferation with a significant additive effect compared to untreated and control peptide. They entered the cells with different magnitudes. Intensive protein-protein interaction was detected among significantly upregulated proteins. Translation, folding and localization of proteins and RNA processing, apoptosis process was significantly enriched post the treatments. The apoptotic signaling was suggested as a result of tumor necrosis factor-α (TNF-α) pathway activation, indicated by the dose-dependent elevated levels of caspase 3 and caspase 9. The epidermal growth factor receptor and androgen receptor pathways appeared inhibited by the peptides. Moreover, the activation of T-cell receptor derived from the quantitation results further implies the likelihood of recruiting more T cells to the cell growth environment post the treatment and more sensitive to T cell mediated killing of HeLa cells. Our results indicate that caerin 1.1 and 1.9 mediate apoptotic signals of HeLa cells and may subsequently enhances adaptive T cell immune responses.
... However, acute placental inflammation (the only causal link to spontaneous preterm labor [120][121][122][123][124][125][126][127] and present in a subset of women who deliver preterm [128][129][130][131]) decreased the abundance of exhausted T cells at the maternal-fetal interface, suggesting that T cell exhaustion is reduced solely in some cases of preterm labor associated with exacerbated placental inflammation. The mechanisms whereby placental inflammation can reduce T cell exhaustion at the maternal-fetal interface may involve cytokines, given that such inflammatory mediators can reverse T cell dysfunction [73,[132][133][134][135]. Therefore, we surmise that placental inflammation boosts effector T cell function by dampening T cell exhaustion at the maternal-fetal interface in a subset of women who undergo preterm labor. ...
... A central question that arises from this study is whether T cell exhaustion at the maternal-fetal interface can be augmented in order to ameliorate effector T cell responses that lead to pathological inflammation and preterm labor and birth. T cell exhaustion has been manipulated by targeting the TCR and inhibitory receptors (e.g., PD-1, TIM-3, CTLA-4, and LAG-3) as well as by treatment with soluble mediators (e.g., anti-inflammatory cytokines such as IL-10 and TGFβ) and suppressive cells [67,68,[135][136][137][138][139][140][141]. Further research is required to investigate which of the abovementioned strategies could be safely utilized during pregnancy. ...
Successful pregnancy requires a tightly-regulated equilibrium of immune cell interactions at the maternal-fetal interface (i.e., the decidual tissues), which plays a central role in the inflammatory process of labor. Most of the innate immune cells in this compartment have been well characterized; however, adaptive immune cells are still under investigation. Herein, we performed immunophenotyping of the decidua basalis and decidua parietalis to determine whether exhausted and senescent T cells are present at the maternal-fetal interface and whether the presence of pathological (i.e., preterm) or physiological (i.e., term) labor and/or placental inflammation alter such adaptive immune cells. In addition, decidual exhausted T cells were sorted to test their functional status. We found that (1) exhausted and senescent T cells were present at the maternal-fetal interface and predominantly expressed an effector memory phenotype, (2) exhausted CD4⁺ T cells increased in the decidua parietalis as gestational age progressed, (3) exhausted CD4⁺ and CD8⁺ T cells decreased in the decidua basalis of women who underwent labor at term compared to those without labor, (4) exhausted CD4⁺ T cells declined with the presence of placental inflammation in the decidua basalis of women with preterm labor, (5) exhausted CD8⁺ T cells decreased with the presence of placental inflammation in the decidua basalis of women who underwent labor at term, (6) both senescent CD4⁺ and CD8⁺ T cells declined with the presence of placental inflammation in the decidua basalis of women who underwent preterm labor, and (7) decidual exhausted T cells produced IFNγ and TNFα upon in vitro stimulation. Collectively, these findings indicate that exhausted and senescent T cells are present at the human maternal-fetal interface and undergo alterations in a subset of women either with labor at term or preterm labor and placental inflammation. Importantly, decidual T cell function can be restored upon stimulation.
... Besides, soluble mediators have been shown to promote exhaustion, including IL-10 and TGF-b (Li et al. 2006;Brooks et al. 2008;Tinoco et al. 2009;Ni et al. 2015) (Figure 2). To date, TEX cells have been described in tumor mouse models and in numerous cancer entities, including melanoma, chronic myeloid leukemia, non-small cell carcinoma, colorectal cancer, ovarian cancer, Hodgkin lymphoma, and chronic lymphocytic leukemia (Mumprecht et al. 2009;Matsuzaki et al. 2010;Zhang et al. 2010;Baitsch et al. 2011;Schietinger et al. 2016;Zhang et al. 2018b). ...
... Interestingly, Il10rb -/-CD4 + T-cells proliferated similarly to WT CD4 + T-cells, but Il10rb -/-TR1 cells displayed higher expression of PD-1 along with reduced levels of cytotoxic molecules, indicating an enhanced exhaustion phenotype. These results might seem inconsistent with the commonly described immunosuppressive role of IL-10 (Brooks et al. 2006;Ni et al. 2015), but several studies have reported that IL-10 signaling through STAT3 prevents dysfunction in CD8 + T-cells (Naing et al. 2016;Gorby et al. 2020), Hanna et al. unpublished work). Thus, a similar mechanism could be active in CD4 + T-cells. ...
Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm characterized by an accumulation of mature B lymphocytes in blood and peripheral lymphoid organs which highly depend on a tumor-supportive microenvironment. Altered T-cell distribution and function have since long been observed in the CLL microenvironment, but the exact pathological role of the different T-cell subsets remains uncertain. In the present work, the spectrum of CLL-associated T-cell phenotypes were investigated by using leading-edge single-cell technologies. Mass cytometry analyses of lymph nodes (LN), peripheral blood and bone marrow of CLL patients together with reactive lymph nodes (rLNs) of donors without cancer identified the CLL LN as a distinct niche, where CD8+ effector memory T-cells with an exhausted phenotype accumulate. Single-cell transcriptome and TCR-clonality analyses of LN T-cells further revealed a clonal expansion restricted to effector memory CD8+ T-cells, and enabled the characterization of the specific cross-talk between CLL cells and T- cell subsets. Besides, the single-cell transcriptome of T-cells from the Eμ-TCL1 mouse model of CLL was examined and shown to be similar to that of T-cells from CLL patients. Since genome-wide association studies have identified that a single-nucleotide polymorphism affecting the T-cell master regulator EOMES is associated with CLL development, the role of this transcription factor in the disease was investigated. Epigenetic and single-cell RNA sequencing analyses revealed that EOMES is not expressed in CLL cells but in T-cells, and that its levels are highest in exhausted CD8+ T-cells. Interestingly, Eomes deficiency in CD8+ T-cells prevented their expansion and led to a decreased leukemia control in the TCL1 mouse model, providing a novel layer of evidence for an anti-tumor role of CD8+ T-cells in CLL. Furthermore, mass cytometry and single-cell RNA-sequencing analyses revealed an increase of T regulatory type 1 (TR1) CD4+ T-cells in CLL LNs compared to rLNs. Such accumulation was likewise confirmed in spleen of Eμ-TCL1 mice using flow cytometry. Strikingly, TR1 cells failed to expand from Eomes-deficient CD4+ T-cells adoptively transferred in leukemic mice, and consequently were less capable of controlling leukemia development. Moreover, TR1 cell-mediated CLL control required IL-10 receptor signaling, as Il10rb-/- CD4+ T- cells showed impaired anti-leukemia activity. Taken together, the data generated herein comprehensively and deeply characterize the composition and phenotype of the T-cell compartment of CLL patients in comparison to individuals without cancer, and significantly improve our understanding of the function of distinct T-cell subsets in CLL.
... Previous studies showed that IL-6R antagonist tocilizumab could reverse the cytokine storm [33], and specifically blockading the signaling pathways regulated by IL-6 might be a promising method to reduce inflammationrelated injuries and the mortality [34,35]. IL-10 has a major anti-inflammatory effect regulated by JAK-STAT pathway [36], produced by antigen presentation cells (APC) including dendritic cells, macrophages, and Th cells [36,37]. Higher IL-8 levels were found in deceased cases that might induce [38,39]. ...
... IL-10 could also mediate direct effects on T cells, B cells, NK cells, mast cells, and eosinophils [45]. It was reported that IL-10 signaling blockade at the priming stage could induce stronger Ts cell responses, which is beneficial for treatment of chronic viruses and cancer [37]. Our study demonstrated that the depletion of lymphocyte subsets might cause hyperinflammatory response in deceased cases, resulting in overproduction of proinflammatory cytokines and cytokine storm in SARS-CoV-2 infection, which might be part of the immunogenicity of COVID-19. ...
Objective:
To compare the difference of inflammatory cytokines and lymphocyte subsets between deceased patients and survivors with COVID-19.
Methods:
This retrospective study included 254 confirmed patients from 10 January to 11 March, 2020, at Tongji Hospital of Wuhan, China. Laboratory and immunologic features were collected and analyzed, and the main outcomes focused on inflammatory cytokines and lymphocyte subsets.
Results:
A trend of markedly higher levels of inflammatory cytokines as well as lower lymphocyte subset levels in deceased patients was observed compared with survivors. ROC curve analyses indicated that inflammatory cytokines and the decrease levels of T cell, Th (helper T cells) cell, Ts (suppressor T cells) cell, B cell, and NK cell along with Th/Ts ratio increase could be used to predict the death of COVID-19. Multivariate analyses showed that higher levels of IL-6, IL-8, and IL-10 remained significantly correlated with shorter survival time and that the amount of Ts cells was negatively associated with the possibility of death in COVID-19 patients. In conclusion, SARS-CoV-2 would cause lymphopenia and result in decreased lymphocyte subset cells, particularly in Ts cell counts, which further induces hyperinflammatory response and cytokine storm. IL-6, IL-8, IL-10, and Ts cell might be independent predictors for the poor outcome of COVID-19.
... Of these modulators is the immunosuppressive cytokine IL-10, which has been identified as a potential target to reinvigorate exhausted T cells. IL-10 has been reported to be positively associated with persistence of viral infections such as HCV, HIV, and Epstein-Barr virus (EBV), a possible strategy for viruses to evade host immune defenses (49,50). In LCMV infection models, the blockade of IL-10 appears to inhibit viral persistence and enhances T-cell functions (51,52). ...
... Taken together, with the observations of IL-10-mediated regulation of liver inflammation following LCMV infection, treatment with anti-IL-10 should be carefully calibrated to prevent undesirable side-effects (56). This concern also warrants a thorough revisit on the role of IL-10 blockade in immunotherapy (50). ...
T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
... 46 Recently, two peptides designed through computer modelling have been shown to inhibit IL-10 mediated signaling both in vitro and in vivo. [47][48][49] Temporally blocking IL-10 Table 1. Enhancing the efficacy of imiquimod by combining with other therapies. ...
... Mode of Action Synergy with Imiquimod Reference Imiquimod Stimulates innate immune responses and induces apoptosis of HPV infected cells 40,59 Interleukin 10 inhibitor Interleukin 10 signalling blockade Amplify the stimulation of innate immune responses by imiquimod [47][48][49] Natural peptides Inhibits the growth of HPV infected cells, stimulating inflammation signalling pathways Both imiquimod and the natural peptides stimulate innate immune responses, cause apoptosis of HPV infected cells 53 Therapeutic vaccine Generates antigen specific T cells Attracts more antigen specific T cells to the warts 58,60 signaling at the time of immunization in mice does not cause an excessive inflammatory response. 50 These results argue that imiquimod may achieve better efficacy against genital warts if used together with an IL-10 inhibitor. ...
Genital warts are one of the most common sexually transmitted diseases worldwide. The disease is a result of infection with low-risk types of human papillomaviruses, mostly type 6 and 11. Current therapies for genital warts are mainly ablative, or alternatively topical application of imiquimod cream and sinecatechin (polyphenon E) ointment to the warts. However, low patient compliance and high recurrence rate are significant problems for the treatment of genital warts by imiquimod and ablative therapies. We summarise recent literature in this area and propose combining imiquimod with other therapies to increase the efficacy of imiquimod.
... Во время заболеваний, вызванных Staphylococcus aureus, наблюдается повышение экспрессии IL-12, который вместе с IL-17 играет доминирующую роль в патогенезе стафилококковой инфекции [3,79]. Quang-Tam Nguyen и соавт. ...
... Quang-Tam Nguyen и соавт. [79] продемонстрировали наличие зависимости течения стафилококковой пневмонии от уровня продукции IL-12. Установлено, что нокаутные мыши Il12p35 -/-, не экспрессирующие IL-12p35, высокочувствительны к MRSA, а комбинированная терапия линезолидом с экзогенным IL-12 MRSA-индуцированной пневмонии у данных мышей способствует их выживанию практически во всех случаях. ...
... TGF-β, IL-10) by either small molecules or neutralizing antibodies, has shown great results in the treatment of several cancers and should be envisaged for liver pathogens targeting these responses (e.g. HBV) [124][125][126] (Table 1). Additionally, several molecules have been used to target the anti-inflammatory phenotype often displayed by tumour associated macrophages (TAMs), as extensively described by others 127 . ...
Liver macrophages can be both involved in pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) and hepatitis delta virus (HDV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLM) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDM or M2-MDM, respectively). PLM or primary blood monocytes either ex-vivo differentiated into M1-MDM or M2-MDM were exposed to HBV from different genotype and their activation followed by ELISA or RT-qPCR. Liver biopsies from HBV infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes (PHH) and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses. We evidenced the presence of HBc protein within macrophages in liver biopsies from HBV-infected patients and higher levels of anti-inflammatory macrophages markers, compared to non-infected ones. Ex vivo exposure of naive PLM to HBV led to a reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV (from genotype C and D) during differentiation and activation, M1-MDM secreted less IL-6 and IL-1β, whereas M2-MDM secreted more IL-10 when exposed to HBV (from genotype B, C or D) during activation. Using a co-culture approach, we identified HBV envelope particle (HBsAg) as being responsible for the aforementioned modulations of M1-MDMs. As expected, HDV virions, which also display HBsAg, behaved similarly. We also showed that cytokines produced by M1-MDM, but not those produced by HBV-exposed M1-MDM, decreased HBV establishment in hepatocytes. Besides, we observed a strong dose-dependent decrease of HBV RNAs (from genotypes A to E) and HDV RNAs maintenance upon treatment of infected hepatocytes with recombinant IL-1β. This inhibition was shown to be dependent on the activation of the NFkB pathway and would at least involved mechanism targeting HBV RNAs stability. Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favor its establishment and persistence.
... Blockade of the IL-10 receptor (IL-10R) with anti-IL-10 mAbs enhances control of LCMV infection and restores T cell responses (Brooks et al., 2006;Ejrnaes et al., 2006), while simultaneous blockade of IL-10 and PD-1 reverses CD8+ T cell exhaustion, improving HIV control (Wherry, 2011). Furthermore, simultaneous IL-10 blockade during therapeutic DNA vaccination enhanced clearance of chronic LCMV infection (Ni et al., 2015). In the mouse model, the use of antimony, the conventional chemotherapy for visceral leishmaniasis, in conjunction with anti-IL-10R treatment permitted a considerable reduction in duration and dosage of treatment (Weiner et al., 2012). ...
The advances in cancer biology and pathogenesis during the past two decades, have resulted in immunotherapeutic strategies that have revolutionized the treatment of malignancies, from relatively non-selective toxic agents to specific, mechanism-based therapies. Despite extensive global efforts, infectious diseases remain a leading cause of morbidity and mortality worldwide, necessitating novel, innovative therapeutics that address the current challenges of increasing antimicrobial resistance. Similar to cancer pathogenesis, infectious pathogens successfully fashion a hospitable environment within the host and modulate host metabolic functions to support their nutritional requirements, while suppressing host defenses by altering regulatory mechanisms. These parallels, and the advances made in targeted therapy in cancer, may inform the rational development of therapeutic interventions for infectious diseases. Although “immunotherapy” is habitually associated with the treatment of cancer, this review accentuates the evolving role of key targeted immune interventions that are approved, as well as those in development, for various cancers and infectious diseases. The general features of adoptive therapies, those that enhance T cell effector function, and ligand-based therapies, that neutralize or eliminate diseased cells, are discussed in the context of specific diseases that, to date, lack appropriate remedial treatment; cancer, HIV, TB, and drug-resistant bacterial and fungal infections. The remarkable diversity and versatility that distinguishes immunotherapy is emphasized, consequently establishing this approach within the armory of curative therapeutics, applicable across the disease spectrum.
... The IL-1 family is essential for initiation of the inflammatory cascade (25,26), and cytokines in the IL-6 family have both immunoregulatory, as well as other systemic effects (27). The main anti-inflammatory cytokines include those in the IL-10 (28) and IL-12 families (29)(30)(31)(32). ...
The inflammatory response is a well-established part of, and a prerequisite for, venous thrombosis. To better understand the pathophysiology of venous thrombosis and to identify improved diagnostic biomarkers, further studies of the relationship between inflammation and coagulation are needed. We review previous studies concerning inflammatory biomarkers in venous thromboembolism, in particular cytokines, soluble adhesion molecules and matrix metalloproteases as predisposing, diagnostic and prognostic factors in venous thrombosis. Elevated cytokines and genetic alterations coding for cytokines are found in several patient cohorts which indicate that cytokines are involved as predisposing factors in venous thrombosis development. Increased levels of pro-inflammatory cytokines are detected both in animal models and in patients with acute venous thrombosis and clinical trials, although currently without evident diagnostic value. Adhesion molecules are crucial in the development of venous thrombosis, especially P-selectin seems important in initiating leukocyte accumulation and adhesion to endothelium for subsequent platelet accumulation. Several studies have demonstrated increased soluble P-selectin levels in patients with venous thrombosis, emphasizing its potential role as diagnostic marker and also as a therapeutic target. Matrix metalloproteases are essential effectors during venous thrombosis resolution and may impact vessel wall fibrosis, and together with their natural occurring inhibitors are crucial in acute and chronic thrombosis pathophysiology. Furthermore, studies in animal models of venous thrombosis have demonstrated anti-inflammatory treatment to be effective in terms of thrombus resolution and reduction of vessel wall damage, without increase in bleeding risk during the course of treatment. Thus, soluble mediators should be further investigated both as possible biomarkers and therapeutic targets in venous thromboembolic disease.
... When considering VL-HIV coinfection, these data would advocate the blocking of excessive IL-10 levels during the acute stage of VL in HIV patients (in particular pre-ART patients) to allow a beneficial acute response which should however be time limited to retain the beneficial role of IL-10 in controlling side damage of chronic HIV and parasitic infections. To reduce the unwanted side effects due to blockage of normal, and beneficial, biological activities, novel IL-10 signaling inhibitors with for instance shorter half-lives are first needed (122). ...
Patients with visceral leishmaniasis (VL)–human immunodeficiency virus (HIV) coinfection
experience increased drug toxicity and treatment failure rates compared to VL patients,
with more frequent VL relapse and death. In the era of VL elimination strategies, HIV
coinfection is progressively becoming a key challenge, because HIV-coinfected patients
respond poorly to conventional VL treatment and play an important role in parasite
transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic
drugs, new interventions that target host immunity may offer an effective alternative. In
this review, we first summarize current views on how VL immunopathology is significantly
affected by HIV coinfection. We then review current clinical and promising preclinical
immunomodulatory interventions in the field of VL and discuss how these may operate
in the context of a concurrent HIV infection. Caveats are formulated as these interventions
may unpredictably impact the delicate balance between boosting of beneficial
VL-specific responses and deleterious immune activation/hyperinflammation, activation
of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to
prioritize a target molecule and a more detailed account of the immunological status
induced by the coinfection as well as surrogate markers of cure and protection are
still required. We do, however, argue that virologically suppressed VL patients with a
recovered immune system, in whom effective antiretroviral therapy alone is not able to
restore protective immunity, can be considered a relevant target group for an immunomodulatory
intervention. Finally, we provide perspectives on the translation of novel
theories on synergistic immune cell cross-talk into an effective treatment strategy for
VL–HIV-coinfected patients.
... Antiviral drugs that target host proteins instead of viral proteins could in theory minimize the emergence of resistance (66). IL-10 immune therapy is the focus of many clinical trials for the treatment of inflammatory diseases (67)(68)(69)(70). Because there are no therapeutic interventions for viral encephalomyelitis, understanding the potential of IL-10 as a therapeutic agent remains important. ...
Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash, and encephalomyelitis. Previous studies in mice with a virulent strain (neuroadapted SINV [NSV]) of the alphavirus Sindbis virus (SINV) identified a role for Th17 cells and regulation by interleukin-10 (IL-10) in the pathogenesis of fatal encephalomyelitis (K. A. Kulcsar, V. K. Baxter, I. P. Greene, and D. E. Griffin, Proc Natl Acad Sci U S A 111:16053–16058, 2014, https://doi.org/10.1073/pnas.1418966111). To determine the role of virus virulence in generation of immune responses, we analyzed the modulatory effects of IL-10 on disease severity, virus clearance, and the CD4⁺ T cell response to infection with a recombinant strain of SINV of intermediate virulence (TE12). The absence of IL-10 during TE12 infection led to longer morbidity, more weight loss, higher mortality, and slower viral clearance than in wild-type mice. More severe disease and impaired virus clearance in IL-10−/− mice were associated with more Th1 cells, fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells, and B cells, and delayed production of antiviral antibody in the central nervous system (CNS) without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain.
IMPORTANCE
Alphaviruses cause mosquito-borne outbreaks of encephalomyelitis, but determinants of outcome are incompletely understood. We analyzed the effects of the anti-inflammatory cytokine IL-10 on disease severity and virus clearance after infection with an alphavirus strain of intermediate virulence. The absence of IL-10 led to longer illness, more weight loss, more death, and slower viral clearance than in mice that produced IL-10. IL-10 influenced development of disease-causing T cells and entry into the brain of B cells producing antiviral antibody. The Th1 pathogenic cell subtype that developed in IL-10-deficient mice infected with a less virulent virus was distinct from the Th17 subtype that developed in response to a more virulent virus, indicating a role for virus strain in determining the immune response. Slow production of antibody in the nervous system led to delayed virus clearance. Therefore, both the virus strain and the host response to infection are important determinants of outcome.
... Therapeutic vaccine targeting viral infected or cancer cells without hurting normal tissues or organs, is a potential therapeutic for the treatment of chronic HPV infection and HPV infection related cancers, by stimulating cytotoxic T cells (CTLs) against viral/tumour antigens [9]. The HPV early proteins E6 and E7 are expressed in HPVassociated cancers and are ideal targets for a therapeutic vaccine [10,11]. ...
Background
Cancer therapeutic vaccine induced cytotoxic T cell (CTL) responses are pivotal for the killing of tumour cells. Blocking interleukin 10 (IL-10) signalling at the time of immunization increases vaccine induced CTL responses and improves prevention of tumour growth in animal models compared to immunization without an IL-10 signalling blockade. Therefore, this immunization strategy may have potential to curtail cancer in a clinical setting. However, IL-10 deficiency leads to autoimmune disease in the gut. Blocking IL-10 at the time of immunization may result in unwanted side effects, especially immune-pathological diseases in the intestine. Methods
We investigated whether blocking IL-10 at the time of immunization results in intestinal inflammation responses in a mouse TC-1 tumour model and in a NOD autoimmune disease prone mouse model. ResultsWe now show that blocking IL-10 at the time of immunization increases IL-10 production by CD4+ T cells in the spleen and draining lymph nodes, and does not result in blood cell infiltration to the intestines leading to intestinal pathological changes. Moreover, immunization with papillomavirus like particles combined with simultaneously blocking IL-10 signalling does not increase the incidence of autoimmune disease in Non-obese diabetic (NOD) mice. Conclusions
Our results indicate that immunization with an IL-10 inhibitor may facilitate the generation of safe, effective therapeutic vaccines against chronic viral infection and cancer.
... Concerning immunotherapeutic intentions, we think a combination of PEG-IL-10 and PD1-antagonists could have a synergistic effect and might be a potent weapon against the devastating effect of tumoural PDL1 in NSCLC (Naing et al, 2016b), whereas PEG-IL-10 might be less useful in SCC, but especially useful in ADC. Besides those two, other antibody strategies would be thinkable according to our tumour model like the use of PDL1-AB (Antonia et al, 2016), IL10R-AB (Ni et al, 2015;Chen et al, 2016a) and IL-10-AB, whereupon current used IL-10-AB do not decrease but increase the level of IL-10 and are not used yet in NSCLC (Llorente , 2000). Furthermore, beside those primarily therapeutic intentions, IL-10 could possibly be used as a diagnostic parameter in ADC for anti-PD1/PDL1 treatment success forecast, whereas lower levels of IL-10 might go along with a lower anti-PD1/PDL1 resistance and better prognosis. ...
Background:
Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape.
Methods:
Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer.
Results:
Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3(+) T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis.
Conclusions:
These new findings suggest that IL-10 counteracts IFN-γ effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.British Journal of Cancer advance online publication 10 October 2017 doi:10.1038/bjc.2017.336 www.bjcancer.com.
... In addition, the use of neutralizing IL-10 antibodies in combination with therapeutic vaccination enhanced CD8 and CD4 T cell responses and reduced viral load (144). Similar approaches are being investigated for cancer immunotherapy (23,152). TGF-β has also been implicated in promoting T cell exhaustion. ...
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
... These include a wide variety of TNF-α blockers (e.g., infliximab, etanercept, and adalimumab among others) for the treatment of many different autoimmune conditions including Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, and ankylosing spondylitis (65); the IL-1 receptor antagonist anakinra approved for the treatment of rheumatoid arthritis (66) and moving through late stage clinical trials for the treatment of other autoimmune conditions; IL-4/IL-13 receptor antagonists (lebrikizumab, pitrakinra, dupilumab, tralokinumab) currently in clinical trials for the treatment of asthma (67,68), and IL-2 receptor antagonists used to treat multiple sclerosis (daclizumab) (69) and prevent transplant rejection (basiliximab) (70). Efforts at aimed at direct blocking of IL-10 signaling, while promising in experimental model systems, remain in preclinical stages of development at present (71). In contrast, there exist an enormous number of peptides, anti-sense oligonucleotides, monoclonal antibodies, and small molecule inhibitor drugs in various stages of clinical development that are designed to block TGF-β signaling in a variety of different ways (72,73). ...
At the turn of the last century, the emerging field of medical oncology chose a cytotoxic approach to cancer therapy over an immune-centered approach at a time when evidence in support of either paradigm did not yet exist. Today, nearly 120 years of data have established that (a) even the best cytotoxic regimens only infrequently cure late-stage malignancy and (b) strategies that supplement and augment existing antitumor immune responses offer the greatest opportunities to potentiate durable remission in cancer. Despite widespread acceptance of these paradigms today, the ability of the immune system to recognize and fight cancer was a highly controversial topic for much of the twentieth century. Why this modern paradigmatic mainstay should have been both dubious and controversial for such an extended period is a topic of considerable interest that merits candid discussion. Herein, we review the literature to identify and describe the watershed events that ultimately led to the acceptance of immunotherapy as a viable regimen for the treatment of neoplastic malignancy. In addition to noting important clinical discoveries, we also focus on research milestones and the development of critical model systems in rodents and dogs including the advanced modeling techniques that allowed development of patient-derived xenografts. Together, their use will further our understanding of cancer biology and tumor immunology, allow for a speedier assessment of the efficacy and safety of novel approaches, and ultimately provide a faster bench to beside transition.
... Actually, an increased pro-inflammatory profile undoubtedly leads to the elevation of the serum concentration of IL-18 as an important cytokine for initiating and perpetuating the catabolic and inflammatory responses in the patients with SA [24]. IL-18 can also act as a co-inducer of the T-helper 2 (Th2) cytokine IL-10 from IL-6 fostered T cells and basophils [25,26]. Therefore, the over-expression of the IL-18 could be one of the reasons for a significant increase in serum levels of IL-10 in the patients with SA. ...
... The IL-10 median was higher in GBM (p = 0.0006). In addition to immune suppression, a direct effect of IL-10 on GBM proliferation has been reported [20,21]. Higher ferritin was also detected in GBM patients (p < 0.0001) and may be related to tumor-associated changes in iron hemostasis [22] as well as macrophage activation, which has also been documented by investigating macrophage infiltration in GBM tissue [23]. ...
Background
Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. Methods
Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. ResultsUsing descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. Conclusions
Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.
... In vivo inhibition of IL-10 signalling can be achieved through administration of anti-IL-10R antibodies [15,16]. However, clinical grade humanized antibodies are not available for clinical use [17]. ...
Blockade of IL-10 signalling clears chronic viral and bacterial infections. Immunization together with blockade of IL-10 signalling or relatively low level of IL-10 further enhances viral and bacterial clearance. IL-10 functions through binding to interleukin 10 receptor (IL-10R). Here we showed that peptides P1 and P2 with the hydrophobic and hydrophilic pattern of the IL10R-binding helix in IL-10 could bind with either IL-10R1 or IL-10, and inhibit inflammatory signals with long duration and negligible cytotoxicity in vitro. Furthermore, P2 can enhance antigen specific CD8+ T cell responses in mice induced by the vaccine based on a long peptide of protein E7 in a human papillomavirus type 16.
... A great number of cytokines have been identified in humans, and their functions have been widely studied in animal models and human cells. Several cytokines have proved effective in the clinical treatment of specific diseases [3][4][5][6][7] . Understanding the molecular mechanism of cytokine function will help us better examine and treat different disease conditions. ...
Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, is a heterodimeric cytokine. It is composed of subunits p40 (shared with IL-12) and p19 (an IL-12 p35-related subunit) and is secreted by several types of immune cells, such as natural killer cells and dendritic cells. The IL-23 receptor is composed of the subunit IL-12Rβ1 and the IL-23-specific subunit IL-23R. The binding of IL-23 to its specific cell surface receptor regulates a number of functions, including proliferation and differentiation of cells and secretion of cell factors. Memory T cells are a subset of T cells that secrete numerous important cell factors, and they function in the immune response to infection and diseases like cancer, autoimmune disease and bronchial asthma. IL-23R is expressed on the surface of memory T cells, which suggests that it can specifically regulate memory T cell function. IL-23 has been widely used as a clinical indicator in immune-related diseases and shows potential for use in disease treatment. Here we review the current progress in the study of the role of IL-23 in the regulation of memory T cells.
... Once activated, IL-10 receptor mitigates inflammatory signaling in many innate and adaptive immune cells [44]. Moreover, in addition to IL-10, IL-11 is another cytokine with a pleiotropic effect on various immune cells and can abrogate pro-inflammatory factors release including nitric oxide, TNF-a and IL-1b by activated macrophages, and inhibits production of IL-2 and IFN-c. ...
Objective:
Human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are well known to modulate T cells. However, the molecular mechanisms that mark hBM-MSCs immunomodulation of T cells are not fully resolved.
Materials and methods:
hBM-MSCs harvested from sternum or iliac crest of five healthy donors and characterized in accordance with the International Society of Cellular Therapy (ISCT) guidelines are co-cultured with T cells. Additionally, modulatory effects of MSCs on T-cell viability, proliferation, cytokine profile, co-stimulatory pathway, activation and immunomodulation are also determined.
Results:
hBM-MSCs significantly reduced the expression of T-cell activation marker CD38 as well as co-stimulatory markers CD134 and CD154, whilst that of CD27 remained unchanged. BrdU, CFSE and Ki67 proliferation assays showed that hBM-MSCs reduced T-cell proliferation. Moreover, viability of T cells remained unchanged when co-cultured with hBM-MSCs. Finally, T cells when co-cultured with hBM-MSCs showed increased secretion of IL-10 and IL-11.
Conclusion:
Collectively, hBM-MSCs are able to modulate the main steps involved in T-cell response toward a tolerogenic state. Thus, establishing immunobiological criteria defining the immunosuppressive effect of hBM-MSCs is of importance to reach efficient immunotherapeutic intervention.
... The production of TGF-β by the fibroblasts in the tumor microenvironment impairs the host response to ICPis-another key tumor factor that presents opportunities for therapeutic targeting [55]. Other immunosuppressive cytokines play key roles as well in blocking the response to ICPis [56,57]. A preclinical study showed that blocking both IL-6 and TGF-β enhanced the activity of ICPis [58]. ...
Immune checkpoint inhibitors (ICPis) have revolutionized cancer therapy with broad activities against a wide range of malignancies. However, in many malignancies their efficacy remains limited due to the primary resistance. Furthermore, a high percentage of patients develop progression due to the secondary resistance even after obtaining a response or achieving a stable disease. In this review, we will discuss the mechanisms that underlie the primary and secondary resistance to ICPis in cancer immunotherapy and provide an overview to impart a broad understanding of the critical issues that are encountered in clinical oncology practice.
... The function of such vectors may be based on different mechanisms. Blocking interleukin 10 (IL10) production at the time of immunization to increase cytotoxic T-cell responses in antigen-experienced host is one of them [115,116]. Ni et al. demonstrated that GO could absorb anti-IL10 receptor antibodies. Interleukin 10 is an antiinflammatory cytokine that limits immune responses to both self and foreign antigens. ...
Nanoparticles (NPs) are atomic clusters of crystalline or amorphous structure that possess unique physical and chemical properties associated with a size range of between 1 and 100 nm. Their nano-sized dimensions, which are in the same range as those of vital biomolecules, such as antibodies, membrane receptors, nucleic acids, and proteins, allow them to interact with different structures within living organisms. Because of these features, numerous nanoparticles are used in medicine as delivery agents for biomolecules. However, off-target drug delivery can cause serious side effects to normal tissues and organs. Considering this issue, it is essential to develop bioengineering strategies to significantly reduce systemic toxicity and improve therapeutic effect. In contrast to passive delivery, nanosystems enable to obtain enhanced therapeutic efficacy, decrease the possibility of drug resistance, and reduce side effects of “conventional” therapy in cancers. The present review provides an overview of the most recent (mostly last 3 years) achievements related to different biomolecules used to enable targeting capabilities of highly diverse nanoparticles. These include monoclonal antibodies, receptor-specific peptides or proteins, deoxyribonucleic acids, ribonucleic acids, [DNA/RNA] aptamers, and small molecules such as folates, and even vitamins or carbohydrates.
... Plasmid-based therapy offers some advantages, as DNA vaccines are considered safe, stable, relatively inexpensive and feasible for use in humans, particularly when administered by in vivo electroporation [23]. Furthermore, repeated administrations of anti-IL-10 neutralizing antibodies may have side effects, such as chronic gastrointestinal inflammation [24]. Other therapeutic strategies have been shown that blocking IL-10R can increase the potency of antitumoral effects. ...
The presence of IL-10, produced either by tumor cells or immunosuppressive cells, is frequently associated with a poor prognosis for cancer progression. It may also negatively impact anticancer treatments, such as immunotherapies, that otherwise would promote the activation of cytotoxic T cells capable of detecting and destroying malignant cells. In the present study, we evaluated a new adjuvant approach for anticancer immunotherapy using a plasmid vector encoding a soluble form of the IL-10 receptor (pIL-10R). pIL-10R was coadministered to mice with a DNA vaccine encoding the type 16 human papillomavirus (HPV-16) E7 oncoprotein genetically fused with glycoprotein D of herpes simplex virus (HSV) (pgDE7h). Immunization regimens based on the coadministration of pIL-10R and pgDE7h enhanced the antitumor immunity elicited in mice injected with TC-1 cells, which express HPV-16 oncoproteins. The administration of the DNA vaccines by in vivo electroporation further enhanced the anticancer effects of the vaccines, leading to the activation of tumor-infiltrating polyfunctional E7-specific cytotoxic CD8+ T cells and control of the expansion of immunosuppressive cells. In addition, the combination of immunotherapy and pIL-10R allowed the control of tumors in more advanced growth stages that otherwise would not be treatable by the pgDE7h vaccine. In conclusion, the proposed treatment involving the expression of IL-10R enhanced the antitumor protective immunity induced by pgDE7h administration and may contribute to the development of more efficient clinical interventions against HPV-induced tumors.
... It is usually secreted by immune cells, such as monocytes, T cells, macrophages (if stimulated appropriately), certain subsets of dendritic cells, and B cells. 8,9 The human IL10 gene, containing five exons, is located on chromosome 1q32.1. The promoter region contains at least 40 polymorphic sites, and these sites may affect gene transcription. ...
Objective
To evaluate the correlation between interleukin 10 (IL-10) −1082A/G polymorphism (rs1800896) and breast cancers by performing a meta-analysis.
Methods
The Embase and Medline databases were searched through 1 September 2018 to identify qualified articles. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were applied to evaluate associations.
Results
In total, 14 case-control studies, including 5320 cases and 5727 controls, were analyzed. We detected significant associations between the IL10 −1082 G/G genotype and risk of breast cancer (AA + AG vs. GG: OR = 0.88, 95% CI = 0.80–0.97). Subgroup analyses confirmed a significant association in Caucasian populations (OR = 0.89, 95% CI = 0.80–0.99), in population-based case-control studies (OR = 0.87, 95% CI = 0.78–0.96), and in studies with ≥500 subjects (OR = 0.88, 95% CI = 0.79–0.99) under the recessive model (AA + AG vs. GG). No associations were found in Asian populations.
Conclusions
The IL10 −1082A/G polymorphism is associated with an increased risk of breast cancer. The association between IL10 −1082 G/G genotype and increased risk of breast cancer is more significant in Caucasians, in population-based studies, and in larger studies.
... MPV vaccine showed the most convenient basal profile of immune modulation regarding protection at PV1 showing the highest IL-4 expression, significant TNF and IFN-γ increases and lowest IL-10 expression. IL-10 has been described to have a role in immune tolerance 57 and the blockage of IL-10 during immunization has demonstrated better pathogen clearance results in some studies 58 . The results of our study could support the idea that maintaining IL-10 levels low during immunization could be a good approach to avoid mucosal tolerance of Map. ...
Mycobacterium avium subsp. paratuberculosis (Map) causes paratuberculosis (PTB), a granulomatous enteritis in ruminants that exerts high economic impact on the dairy industry worldwide. Current vaccines have shown to be cost-effective against Map and in some cases confer beneficial non-specific effects against other pathogens suggesting the existence of trained immunity. Although Map infection is mainly transmitted by the fecal-oral route, oral vaccination has not been deeply studied. Therefore, the aim of this study was to compare the oral route with a set of mycobacterial and non-mycobacterial vaccines with a subcutaneously administered commercially available vaccine. Training effects on polymorphonuclear neutrophils (PMNs) and homologous and heterologous in vivo protection against Map were investigated in the rabbit infection model. Oral vaccination with inactivated or live vaccines was able to activate mucosal immunity as seen by elevation of serum IgA and the expression of IL4 in peripheral blood mononuclear cells (PBMCs). In addition, peripheral PMN phagocytosis against Map was enhanced by vaccination and extracellular trap release against Map and non-related pathogens was modified by both, vaccination and Map-challenge, indicating trained immunity. Finally, PBMCs from vaccinated animals stimulated in vitro with Map antigens showed a rapid innate activation cytokine profile. In conclusion, our data show that oral vaccination against PTB can stimulate neutrophil activity and both innate and adaptive immune responses that correlate with protection.
... Interleukin 10 (IL-10) is a cytokine expressed by numerous cell types, including innate and adaptive immune cells 66 . Its expression is precisely controlled in cells by transcriptional and post-transcriptional regulations. ...
Natural killer/T-cell lymphoma (NKTCL) is a highly invasive subtype of non-Hodgkin lymphoma, typically positive for cytoplasmic CD3, CD56, cytotoxic markers, including granzyme B and TIA1, and Epstein-Barr virus (EBV). The current treatment methods for NKTCL are associated with several drawbacks. For example, chemotherapy can lead to drug resistance, while treatment with radiotherapy alone is inadequate and results in frequent relapses. Moreover, hematopoietic stem cell transplantation exhibits limited efficacy and is not well recognized by domestic and foreign experts. In recent years, immunotherapy has shown good clinical results and has become a hot spot in cancer research. Clinical activity of targeted antibodies, such as daratumumab (anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody), have been reported in NKTCL. Additionally, dacetuzumab and Campath-1H have demonstrated promising results. Further encouraging data have been obtained using checkpoint inhibitors. The success of these immunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL. Furthermore, anti-CCR4 monoclonal antibodies (mAbs) exert cytotoxic actions on both CCR4+ tumor cells and regulatory T cells. Depletion of these cells and the long half-life of anti-CCR4 mAbs result in enhanced induction of antitumor effector T cells. The role of IL10 in NKTCL has also been investigated. It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies. Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promising results and sustained remission. Cellular immunotherapy may be used either as maintenance therapy following initial induction chemotherapy or in cases of relapsed/refractory disease. The present review outlines the known immunotherapy targets for the treatment of NKTCL.
... The inhibitory effect on T cells could be overcome by decreasing the amount of immunosuppressive signals, which could be accomplished by blocking receptor-ligand interactions for these molecules. Several studies have been published reporting improved T-cell effector function after blocking adenosine, arginase, IDO, IL-10 and TGF-β [176][177][178][179][180][181]. CD3-BsAb therapy has thus far only been combined preclinically with IDO blockade. ...
Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of the CD3-bispecific antibody therapy field and identify intrinsic hurdles in solid cancers. Furthermore, we describe potential combinatorial approaches to overcome these challenges in order to generate selective and more effective responses.
... Therefore, the selection of target cells and treatment targets is critical. Due to uncertain therapeutic safety and effectiveness, IL-10 signaling blockades remaina region for explorationand are being used in cancer immunotherapy [223]. The effect of a specific blockade of IL-10R on the CD4 + T cell response against hepatitis C virus antigens was evaluated in an ex vivo clinical trial [224]. ...
Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects.
... This discrepancy may be caused by the type of reaction where DD has been applied (pathogenesis of AERD) and by the fact that serum levels were not evaluated in this study. IL-10 is an important regulatory and anti-inflammatory cytokine, largely studied and involved in successful allergen immunotherapy (AIT) (Ni et al., 2015). Studies involving AIT showed the role for IL-10 production by T cells (Treg) and B cells (Breg) in inducing tolerance (Akdis et al., 2005, van de Veen, 2017. ...
Drug desensitization (DD) allows transient clinical tolerance to the drug in reactive patients and it is frequently and successfully used in the management of both IgE and non IgE-mediated hypersensitivity reactions (HRs). The underlying mechanisms behind this process is not well understood. The desensitization procedure is associated with the inhibition of mast cells degranulation and cytokine production, that, is attributable, at least partially, to the abrogation of Ca2+ mobilization; in vitro findings and in vivo mouse models of rapid desensitization show that the organization and spatial distribution of actin is critical for Ca2+ mobilization. Some clinical observations may suggest the induction of a longer memory of tolerance by DD and they raise the suspicion that other cells and mechanisms are involved in DD. Some data are emerging about the modifications of immune responses during DD in patients with previous immediate HRs. In particular, an increase of regulatory cytokines, mainly represented by IL-10, has been shown, and more importantly, the appearance of IL-35 producing T regulatory cells has been described during DD. The release of controlled cellular mediators by mast cells over time and the development of the antigen-specific regulation of adaptive response allow to safely and successfully reach the target dose of a first line drug during DD.
... For example, IL-10 is widely recognized as an immunosuppressive cytokine, but there is increasing evidence that it has a dual role in antitumor immunity. Blocking or activation of IL-10 has been proven as an efficient way to enhance antitumor immunity in different aspects (Ni et al., 2015;Naing et al., 2018). According to our results, we believe that TME phenotypes should be considered as a key factor in further study design to illuminate the remaining mysteries of IL-10. ...
Background: The recent clinical success of immunotherapy represents a turning point in cancer management. But the response rate of immunotherapy is still limited. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, due to the lack of appropriate experimental methods, the reason why the immunotherapeutic resistance still existed on the inflamed tumor microenvironment remains unclear. Materials and Methods: Here, based on single-cell RNA sequencing, we classified the tumor microenvironment into inflamed immunotherapeutic responsive and inflamed non-responsive. Then, phenotype-specific genes were identified to show mechanistic differences between distant microenvironment phenotypes. Finally, we screened for some potential drugs that can convert an unfavorable microenvironment phenotype to a favorable one to aid current immunotherapy. Results: Multiple signaling pathways were phenotypes-specific dysregulated. Compared to non-inflamed microenvironment, the expression of interleukin signaling pathways-associated genes was upregulated in inflamed microenvironment. Compared to inflamed responsive microenvironment, the PPAR signaling pathway-related genes and multiple epigenetic pathways-related genes were, respectively, suppressed and upregulated in the inflamed non-responsive microenvironment, suggesting a potential mechanism of immunotherapeutic resistance. Interestingly, some of the identified phenotype-specific gene signatures have shown their potential to enhance the efficacy of current immunotherapy. Conclusion: These results may contribute to the mechanistic understanding of immunotherapeutic resistance and guide rational therapeutic combinations of distant targeted chemotherapy agents with immunotherapy.
... Therapeutic vaccines, through the induction of Cytotoxic T Lymphocyte (CTLs), specifically kill tumour cells without obvious damage to normal cells and tissues; have become a research hotspot [2]. Previously, it was demonstrated that blocking Interleukin 10 (IL-10) signaling at the time of immunization drastically increase the vaccine induced CTL responses compared with the same vaccine without IL-10 signaling blockade, and the vaccine is able to prevent tumour growth [3][4][5]. ...
The goal of this paper is to investigate whether a 3.0T magnetic resonance scanner with a small animal coil can monitor the orthotopic TC-1 cell Cervical Tumour (CT) growth in mice, and to evaluate the tumour growth prevent effect of Human Papillomavirus (HPV)16E7 peptide-based therapeutic vaccine. The TC-1 cells were implanted into cervical cavity of 52 female C57BL/6J mice (6 experiments), and followed by subcutaneously immunization of HPV16E7 peptide-based with interleukin 10 receptor antibody in 18 mice (3 groups) to observe the efficacy of the therapeutic vaccine. The same Magnetic Resonance Imaging (MRI) equipment and protocols were performed through the entire experiments. Images of each tumour-bearing mice were compared with blank mice to determine when the CTs can be determined by MRI. The Tumour Volume (TV) of each mice was monitored including 3 contrast enhanced tumors. The TV changes were evaluated by comparing the size on the same coronal MR images, and Signal Intensity (SI) measurement was adopted on 6 mice to predict the tumour growth trend. This study showed that the average CTs success rate was 90.38% (47/52), the tumour could be clearly detected on average 10 days. The maximum average SI values of tumour-bearing mice on day 4 was 2447, which was significantly higher than that of the blank mice, and increasing from day4 to day12. This study concluded that clinical 3.0T MRI scanner with small animal coil can be used to monitor the CTs, and to evaluate the CTs growth inhibitory effect of HPV16E7 peptide-based therapeutic vaccine, SI values may be used to predict cervical tumour growth and reliable than visual observation of early tumour images
(PDF) Austin Journal of Radiology. Available from: https://www.researchgate.net/publication/340807342_Austin_Journal_of_Radiology [accessed Apr 21 2020].
... The key finding of our study is that there is a different phenotypic pattern between responders and controllers involving other subsets of cells as phenotypic T NAIVE and T EMRA , with the first pattern being relevant in controllers and the second pattern being relevant in responders. It may be important to broaden this investigation in the future to target the exhausted T-cells associated with HIV progression with the idea to promote the development of novel immunotherapeutic approaches [35,36]. This task will be an impressive one considering the increase of tuberculosis infection rates in areas where the HIV infection seems to be endemic [37]. ...
Objective:
Dynamic changes of cytotoxic T cell responses against Human Immunodeficiency Virus 1 (HIV-1) infection have been the subject of an innovative investigation using antiretroviral therapy (ART). Currently, human CD8 naïve central memory (TCM), effector memory (TEM), and effector memory cells re-expressing CD45RA (TEMRA) T-cells have been thoroughly studied with ART. CD45RA is a marker usually found on naïve T-cells.
Materials and methods:
We performed a longitudinal study of mono-/polyfunctional T-cells in the peripheral blood while targeting three functionally distinct cell populations of CD4+ and CD8+ T-cells (single IL2 and IFN-γ, dual IL2/IFN-γ) in 50 HIV-1 patients. These patients consisted of 5 controllers, 15 non-controllers, 20 ART responders, and 10 highly active antiretroviral therapy (HAART) non-responders.
Results:
We found that (1) non-controllers had the highest rate of IFN-γ-expressing CD4 or CD8, but the lowest rate of IL2-producing CD4 or CD8. (2) The control of HIV-1 infection was associated with polyfunctional Gag-specific T cell responses in controllers and responders. (3) Non-responders had high serum levels of IL2 and IFN-γ. There was a high percentage of CD4+ T cell response cells within the less differentiated phenotype in controllers. CD8+ T cell showed a high rate of TEM and TEMRA in responders.
Conclusion:
High levels of pro-inflammatory cytokines are typical in non-responders, exhausted T-cells may be associated with HIV-1 progression.
... Hence, IL-10 plays a paradoxical role in cancer immunotherapy through activation or inhibition of IL-10 signaling (73). Therefore, it is important to select target cells based on treatment goals (74). IL-10 signaling blockades are still under exploration and are a long way from being used in cancer therapy due to unclear therapeutic efficacy and safety. ...
Gut microbiota refers to the diverse community of more than 100 trillion microorganisms residing in our intestines. It is now known that any shift in the composition of gut microbiota from that present during the healthy state in an individual is associated with predisposition to multiple pathological conditions, such as diabetes, autoimmunity, and even cancer. Currently, therapies targeting programmed cell death protein 1/programmed cell death 1 ligand 1 or cytotoxic T-lymphocyte antigen-4 are the focus of cancer immunotherapy and are widely applied in clinical treatment of various tumors. Owing to relatively low overall response rate, however, it has been an ongoing research endeavor to identify the mechanisms or factors for improving the therapeutic efficacy of these immunotherapies. Other than causing mutations that affect gene expression, some gut bacteria may also activate or repress the host's response to immune checkpoint inhibitors. In this review, we have described recent advancements made in understanding the regulatory relationship between gut microbiome and cancer immunotherapy. We have also summarized the potential molecular mechanisms behind this interaction, which can serve as a basis for utilizing different kinds of gut bacteria as promising tools for reversing immunotherapy resistance in cancer.
... HPV related HNSCCs may be prevented by the HPV prophylactic vaccine. HPV16 E7 specific immunotherapy may also benefit HPV+ HNSCC patients, if efficacy of a HPV16 E7 specific immunotherapy is high enough [32][33][34]. The data from the current study suggest that as HPV related HNSCCs account for significant proportions of total HNSCCs in southern China, HPV status should be tested for routinely for HNSCC and preventive and therapeutic procedures against HPV should be considered. ...
Human papillomavirus (HPV) related tumours account for a significant proportion of head and neck squamous cell carcinomas (HNSCCs) in developed countries. They respond better to chemo- and radio-therapy, and have a better stage specific prognosis. To establish their prevalence in China, we assessed a series of histology confirmed HNSCCs collected in Zhejiang and Guangdong provinces by PCR for HPV DNA and by immunohistochemistry for p16 protein status. Among 303 HNSCCs, HPV DNA was detected in 26.4%, with HPV16 DNA in 71% of these. Of HNSCC located in the oropharynx, 38.55% (32/83) were HPV+ve. In this series, p16 status was a relatively poor predictor of HPV status as detected by PCR. The stage specific survival time of HPV+ HNSCCs was significantly longer than for HPV- HNSCC. HPV status should be assessed for oropharyngeal cancers in China to assist with appropriate management, and prophylaxis against HPV infection should be considered to reduce the incidence of this disease.
... There are numerous different types of immunotherapy, including some involving interferons, monoclonal antibodies and inoculation [4]. Although many cancer vaccines prevent cancer from occurring, there are also therapeutic ones that can aid in its treatment, offering hope to those already affected [4,5]. Furthermore, a large number of substances can also be used to increase the effectiveness of immunisation, and these are referred to as adjuvants [4]. ...
Although cancer is a leading cause of death, significant breakthroughs have been made in its treatment in recent years. In particular, increasingly effective cancer vaccines are being developed, including some for colorectal cancer. There are also currently a variety of compounds that can act as adjuvants, such as signalling molecules called cytokines. Other adjuvants target and inhibit the specific mechanisms by which cancers evade the immune system. One of them is a galectin inhibitor, which targets galectins—proteins produced by cancer cells that can cause the death of immune cells. Likewise, immune checkpoint inhibitors affect immune checkpoints—natural host proteins that usually control inflammation but can be exploited by cancers to weaken the body’s defences. Equally, regulatory T cells may contribute to the progression of cancer by inhibiting the functions of other T cells. The main advantages of cancer vaccines include their low toxicity and their ability to strengthen the immune system. Nevertheless, significant limitations include their slow effects and their inability to treat cancer at times due to immunosuppression. Ultimately, ongoing trials provide hope for the development of more effective methods of immunotherapeutic inoculation that can target a greater variety of cancers.
... TGF-β, IL-10) by either small molecules or neutralizing antibodies, has shown great results in the treatment of several cancers and should be envisaged for liver pathogens that target these responses (e.g. HBV) [123][124][125] (Table 1). Additionally, several molecules have been used to target the anti-inflammatory phenotype often displayed by tumour associated macrophages (TAMs), as extensively described by others 126 . ...
In their never‐ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (i.e. modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response, and modulation of immune cells count or phenotype).
... The IL-10 median was higher in GBM (p = 0.0006). In addition to immune suppression, a direct effect of IL-10 on GBM proliferation has been reported [20,21]. Higher ferritin was also detected in GBM patients (p < 0.0001) and may be related to tumor-associated changes in iron hemostasis [22] as well as macrophage activation, which has also been documented by investigating macrophage infiltration in GBM tissue [23]. ...
Small molecule inhibitors have proven useful in the treatment of a variety of tumors, but they are often limited by unsustainable benefits and confer resistance quickly. Immunotherapy can result in durable clinical responses, but activity only occurs in a minority of patients. The unfavorable tumor microenvironment (TME) is an important factor limiting immunotherapy. An appropriate understanding of how small molecule inhibitors modulate the TME may optimize the combination of targeted treatment and immunotherapy in managing tumors. In this study, we found that transient treatment with sunitinib malate inhibited the disorganized extension of tumor vessels, pericytes and collagen IV but increased the relative ratio of pericyte-wrapping blood vessels with alleviated hypoxia in tumors, which resulted from tumor vascular normalization. Sunitinib malate increased infiltration of CD8+ T cells and decreased regulatory T cells (Tregs), accompanied by inhibited expression of TGF-β1 and IL-10 and increased CCL-28, IFN-γ and IL-12, but no significant inhibition of myeloid-derived suppressor cells (MDSCs) was observed. In addition, sunitinib malate increased the levels of PD-1 and PD-L1 in TME, combined with anti-PD-1 therapy showed a significant reduction in tumor burden compared with either monotherapy, suggesting that anti-PD-1 therapy is reasonable after sunitinib malate treatment.
Background
Therapeutic intervention targeting immune cells have led to remarkable improvements in clinical outcomes of tumor patients. However, responses are not universal. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, due to the lack of appropriate experimental methods, the reason why the immunotherapeutic resistance still existed on the inflamed tumor microenvironment remains unclear.
Materials and methods
Here, based on integrated single-cell RNA sequencing technology, we classified tumor microenvironment into inflamed immunotherapeutic responsive and inflamed non-responsive. Then, phenotype-specific genes were identified to show mechanistic differences between distant TME phenotypes. Finally, we screened for some potential favorable TME phenotypes transformation drugs to aid current immunotherapy.
Results
Multiple signaling pathways were phenotypes-specific dysregulated. For example, Interleukin signaling pathways including IL-4 and IL-13 were activated in inflamed TME across multiple tumor types. PPAR signaling pathways and multiple epigenetic pathways were respectively inhibited and activated in inflamed immunotherapeutic non-responsive TME, suggesting a potential mechanism of immunotherapeutic resistance and target for therapy. We also identified some genetic markers of inflamed non-responsive or responsive TME, some of which have shown its potentials to enhance the efficacy of current immunotherapy.
Conclusion
These results may contribute to the mechanistic understanding of immunotherapeutic resistance and guide rational therapeutic combinations of distant targeted chemotherapy agents with immunotherapy.
Blocking cytokine interleukin 10 (IL-10) at the time of immunisation enhances vaccine induced T cell responses and improves control of tumour cell growth in vivo. However, the effect of an IL-10 blockade on the biological function of macrophages has not been explored. In the current paper, a macrophage precursor cell line, U937 cells, was selected to investigate the differential expression of proteins and relevant cell signalling pathway changes, when stimulated with lipopolysaccharide (LPS) in the presence of antibodies to IL-10 or IL-10 receptor. We used a quantitative proteomic strategy to investigate variations in protein profiles of U937 cells following the treatments with LPS, LPS plus human anti-IL10 antibody and anti-IL10R antibody in 24hrs, respectively. The LPS treatment significantly activated actin-related cell matrix formation and immune response pathways. The addition of anti-IL10 and anti-IL10R antibody further promoted the immune response and potentially effect macrophage survival through PI3K/AKT signalling; however, the latter appeared to also upregulated oncogene XRCC5 and Cajal body associated processes. © 2019 Ni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Immune checkpoints are accessory molecules that either promote or inhibit T cell activation. Two inhibitory molecules, cytotoxic T cell antigen 4 (CTLA-4) and programmed death 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non-small-cell lung cancer, renal cell cancers, hypermutated gastro-intestinal cancers and others. Immune responses, whether directed against infections or against tumors, are divided into two phases: an initiation and activation phase, where the immune system recognizes a danger signal and becomes activated by innate signals to fight the danger. This reaction is fundamental for the control of infections and cancer, but needs to be turned off once the danger is controlled, as persistence of this activation ultimately causes severe tissue damage. Therefore, each activation of the immune system is followed by a termination phase, where endogenous immune suppressor molecules arrest immune responses to prevent harmful damage. In the case of cancer immune therapies, therapeutic approaches classically enhanced the initiation and activation of immune responses to increase the emergence and the efficacy of cytotoxic T cells (CTL) against cancers. In sharp contrast, immune checkpoint blockade focuses on the termination of immune responses by inhibiting immune suppressor molecules. It thus prevents the termination of immune responses or even awakes those CTLs that became exhausted during an immune response. Therefore, blocking negatively regulating immune checkpoints restores the capacity of exhausted CTL to kill the cancer they infiltrate. In addition, they drive surviving cancer cells into a still poorly defined state of dormancy. As the therapy awakes also self-reactive CTL, one downside of the therapy is the induction of organ-specific autoimmune diseases. The second downside is the exorbitant drug price that withdraws patients at need from a therapy that was developed by academic research that impairs further academic treatment development and financially charges the public health system.
A characteristic feature of African swine fever virus (ASFV) is the ability to escape from host immune response, affecting macrophages and replicating in them. Besides, ASFV - specific antibodies do not completely neutralize the virus. Cytokines are important factors for various viral infection pathologies. The virulence of ASFV isolates may depend on the capacity to regulate cytokine expression by macrophages. Thus, when comparing in vitro and in vivo cytokine production by macrophages, it was established that infection with low virulent virus isolates leads to an immune response with a predominance of cytokines involved in cellular immunity, such as INF-α and IL-12p40, as compared with infection with highly virulent isolates. The aim of this paper was to study the effect of African swine fever virus on the production of IL-10, a pleiotropic cytokine that inhibits synthesis of cytokines and shows a strong antiinflammatory effect. For this, 12 piglets were experimentally infected intramuscularly with a continuous cell culture-adapted ASFV isolate Vero25 at a dose of 10 HAdU per animal followed by control infection of surviving animals with the reference virus isolate Arm 07 at a dose of 1,000 HAdU per animal. Temperature measurements were taken and blood sampling to obtain serum was conducted during the experiment. IL-10 amount in blood sera was determined using Invitrogen test systems (Thermo Fisher, USA). A higher IL-10 level (15.8–173 pg/ml) was observed in blood sera of dead animals infected with a moderately virulent virus, as compared with surviving pigs (4–5 pg/ml). No correlation between the speed of appearance of specific antibodies and IL-10 serum levels has been established. No noticeable effect of the IL-10 serum level prior to infection on the survival rate of animals has been observed. Further studies are needed to establish a causal relationship, including study of the expression of various cytokines during infection with both low- and highly virulent virus isolates.
Nutritional support is an integral part of the supportive care of hematopoietic stem cell transplantation (HSCT) patients. Omega-3 fatty acids (n-3 FA) emulsions in parenteral nutrition (PN) may modify the inflammatory response. The purpose of this study is to compare plasma cytokine levels in children after HSCT using an n-3 FA-containing lipid emulsion (LE) and a soybean oil-based formulation in PN. A randomized double-blind controlled trial was conducted on 14 children following HSCT. Children were randomized to receive either a fish oil or a soybean oil LE. Blood samples were drawn at baseline, on Day 10 and after completion of PN to analyze plasma interleukin 1 beta (IL-1β), 2 (IL-2), 6 (IL-6), 8 (IL-8), 10 (IL-10), and tumor necrosis factor alpha (TNF-α). After 10 days of PN, there were no significant changes in interleukins levels when comparing the two groups or time points (baseline vs. Day 10 of PN). In children requiring PN >21 days, IL-10 and TNF-α levels (P ≤ 0.05) were lower in the fish-oil-containing LE group. Fish oil- and soybean oil-supplemented PN administered for at least 10 days does not cause inflammatory changes. Prolonged PN based on fish oil LE may modulate the inflammatory response.
Introduction
: T cell functions are altered during chronic viral infections and tumor development. This is mainly manifested by significant changes in T cells’ epigenetic and metabolic landscapes, pushing them into an “exhausted” state. Reversing this T cell exhaustion has been emerging as a “game-changing” therapeutic approach against cancer and chronic viral infection.
Areas covered
: This review discusses the cellular pathways related to T cells exhaustion, and the clinical development and possible cellular targets that can be exploited therapeutically to reverse this exhaustion. We searched various databases (e.g. Google scholar, PubMed, Elsevier and other scientific database sites) using the keywords T cell exhaustion, T cell activation, co-inhibitory receptors and reversing T cell exhaustion.
Expert opinion
: The discovery of the immune checkpoints pathways represents a significant milestone towards understanding and reversing T cells exhaustion. Antibodies that target these pathways have already demonstrated promising activities in reversing T cell exhaustion. Nevertheless, there are still many associated limitations. In this context, next generation alternatives are on the horizon. This includes the use of small molecules to block the immune checkpoints’ receptors, combining them with other treatments, and identifying novel, safer and more effective immunotherapeutic targets.
IL-10 signalling blockade by intra-peritoneal injection of anti-IL-10 receptor antibodies at the time of immunization enhances vaccine induced CD8+ T cell responses and promotes bacteria, parasitic and viral control. We now show that blockade of IL-10 signalling at the time of immunization enhances vaccine induced antigen specific CD8+ T cell responses to both dominant and subdominant CTL epitopes. Injection of anti-IL-10 receptor antibodies subcutaneous at the time of immunization also enhances CD8+ T cell responses. Furthermore, IL-10 signalling blockade at the time of a Human papillomavirus 16 E7 peptide /LPS immunization, prevents HPV16 E7 transformed TC-1 tumour growth in mice. Immunization in the presence of anti-IL-10R antibodies and Monophosphoryl lipid A, generates antigen specific CD8+ T cell responses similar to immunization with LPS. Our results suggest that immunization and IL-10 signalling blockade may provide a novel way for the development of therapeutic vaccines against cancer.
Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumorsmay be more effective, particularly those that overcomenatural suppressive factors in the tumor microenvironment.The“TrojanHorse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor
immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that works through IL-10 receptor alpha subunit- and suppresses immune responses in many infectious diseases such as leishmaniasis as well as in cancer. Therefore, in order to restore the host-protective immune responses in such diseases, an antagonist to this cytokine is a pressing need. Herein, using phage peptide library display, we have identified a dodecameric peptide that functions as an antagonist to human IL-10 receptor in an IL-10-induced STAT3 phosphorylation assay. The peptide antagonist’s ability to restore anti-leishmanial function in CD40-activated macrophages was also tested. We observed that the peptide reduced IL-10-induced STAT-3 phosphorylation and enhanced CD40-activated leishmanial functions in macrophages.
Summary Interleukin-10 (IL-10) is a recently described pteiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-t0 suppresses cytokine expression by natu- ral killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulat- ing humoral responses. We here report that injected IL-t0 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human mela- noma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8 + and CD4 + T cells and macrophages at the sites of tumor growth, but abundant NK cells were lo- calized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell--depleted mice). However, IL-t0 downregulation of pro-inflammatory cytokine production and/or recruitment of additional ef- f~ctor cells may also be involved in the anti-tumor effect at higher local concentrations of IL-t0, since transfected B16 tumor cells expressing high amounts of lL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.
Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.
Leishmaniasis, resulting from infection with the protozoan parasite Leishmania, consists of a wide spectrum of clinical manifestations, from healing cutaneous lesions to fatal visceral infections. A particularly severe form of cutaneous leishmaniasis, termed mucosal leishmaniasis, exhibits decreased IL-10 levels and an exaggerated inflammatory response that perpetuates the disease. Using a mouse model of leishmaniasis, we investigated what cytokines contribute to increased pathology when IL-10-mediated regulation is absent. Leishmania major infected C57BL/6 mice lacking IL-10 regulation developed larger lesions than controls, but fewer parasites. Both IFN-γ and IL-17 levels were substantially elevated in mice lacking the capacity to respond to IL-10. IFN-γ promoted an increased infiltration of monocytes, while IL-17 contributed to an increase in neutrophils. Surprisingly, however, we found that IFN-γ did not contribute to increased pathology, but instead regulated the IL-17 response. Thus, blocking IFN-γ led to a significant increase in IL-17, neutrophils and disease. Similarly, the production of IL-17 by cells from leishmaniasis patients was also regulated by IL-10 and IFN-γ. Additional studies found that the IL-1 receptor was required for both the IL-17 response and increased pathology. Therefore, we propose that regulating IL-17, possibly by downregulating IL-1β, may be a useful approach for controlling immunopathology in leishmaniasis.
Priming to Ag can inhibit subsequent induction of an immune response to a new epitope incorporated into that Ag, a phenomenon referred to as original antigenic sin. In this study, we show that prior immunity to a virus capsid can inhibit subsequent induction of the IFN-gamma effector T cell response to a novel CD8-restricted antigenic epitope associated with the virus capsid. Inhibition does not involve Ab to the virus capsid, as it is observed in animals lacking B cells. CD8-restricted virus-specific T cell responses are not required, as priming to virus without CTL induction is associated with inhibition. However, IL-10(-/-) mice, in contrast to IL-10(+/+) mice, generate CD8 T cell and Ab responses to novel epitopes incorporated into a virus capsid, even when priming to the capsid has resulted in high titer Ab to the capsid. Furthermore, capsid-primed mice, unable to mount a response to a novel epitope in the capsid protein, are nevertheless able to respond to the same novel epitope delivered independently of the capsid. Thus, inhibition of responsiveness to a novel epitope in a virus-primed animal is a consequence of secretion of IL-10 in response to presented Ag, which inhibits local generation of new CD8 IFN-gamma-secreting effector T cells. Induction of virus- or tumor Ag-specific CD8 effector T cells in the partially Ag-primed host may thus be facilitated by local neutralization of IL-10.
Various cell types in both lymphoid and non-lymphoid tissues produce the anti-inflammatory cytokine interleukin (IL)-10 during murine cytomegalovirus (MCMV) infection. The functions of IL-10 in the liver during acute infection and the cells that generate this cytokine at this site have not been extensively investigated. In this study, we demonstrate that the production of IL-10 in the liver is elevated in C57BL/6 mice during late acute MCMV infection. Using IL-10 green fluorescence protein (GFP) reporter knock-in mice, designated IL-10-internal ribosomal entry site (IRES)-GFP-enhanced reporter (tiger), NK cells are identified as major IL-10 expressing cells in the liver after infection, along with T cells and other leukocytes. In the absence of IL-10, mice exhibit marked elevations in proinflammatory cytokines and in the numbers of mononuclear cells and lymphocytes infiltrating the liver during this infection. IL-10-deficiency also enhances liver injury without improving viral clearance from this site. Collectively, the results indicate that IL-10-producing cells in the liver provide protection from collateral injury by modulating the inflammatory response associated with MCMV infection.
The aim of this study was to investigate the capacity of an HPV16 E6/E7 synthetic overlapping long-peptide vaccine to stimulate the HPV16-specific T-cell response, to enhance the infiltration of HPV16-specific type 1 T cells into the lesions of patients with HPV16+ high-grade cervical squamous intraepithelial lesion (HSIL) and HPV clearance. This was a placebo-controlled randomized phase II study in patients with HPV16-positive HSIL. HPV16-specific T-cell responses were determined pre- and post-vaccination by ELISPOT, proliferation assay and cytokine assays in PBMC and HSIL-infiltrating lymphocytes, and delayed-type hypersensitivity skin tests. Motivational problems of this patient group to postpone treatment of their premalignant lesions affected the inclusion rates and caused the study to stop prematurely. Of the accrued patients, 4 received a placebo and 5 received 1–2 vaccinations. Side effects mainly were flu-like symptoms and injection site reactions. A strong HPV-specific IFNγ-associated T-cell response was detected by ELISPOT in all vaccinated patients. The outcome of the skin tests correlated well with the ELISPOT analysis. The cytokine profile associated with HPV16-specific proliferation varied from robust type 1 to dominant type 2 responses. No conclusions could be drawn on vaccine-enhanced T-cell infiltration of the lesion, and there was no HPV clearance at the time of LEEP excision. Thus, vaccination of HSIL patients results in increased HPV16-specific T-cell immunity. Further development of this type of treatment relies on the ability to motivate patients and in the reduction in the side effects.
Electronic supplementary material
The online version of this article (doi:10.1007/s00262-012-1292-7) contains supplementary material, which is available to authorized users.
The presence of activated intratumoral T cells correlates clinically with better prognosis in patients with cancer. Although tumor vaccines can increase the number of tumor-specific CD8(+) T cells in systemic circulation, they frequently fail to increase the number of active and tumor reactive T cells within the tumor. Here we show that treatment with the pleiotropic cytokine interleukin-10 (IL-10) induces specific activation of tumor-resident CD8(+) T cells as well as their intratumoral expansion in several mouse tumor models. We found that inhibition of T-cell trafficking from lymphoid organs did not impair IL-10-induced tumor rejection or the activation of tumor-resident CD8(+) T cells. Tumor-resident CD8(+) T cells expressed elevated levels of the IL-10 receptor and were directly activated by IL-10, resulting in prominent phosphorylation of STAT3 and STAT1. Although CD4(+) T cells, regulatory T cells, NK cells, and dendritic cells have been reported as prominent targets of IL-10 in the tumor microenvironment, we found that expression of the IL-10R was required only on CD8(+) T cells to facilitate IL-10-induced tumor rejection as well as in situ expansion and proliferation of tumor-resident CD8 T cells. Together, our findings indicate that IL-10 activates CD8(+) T-cell-mediated tumor control and suggest that IL-10 may represent a potential tumor immunotherapy in human patients with cancer.
Persistent viral infections often overburden the immune system and are a major cause of disease in humans. During many persistent infections, antiviral T cells are maintained in a state of immune exhaustion characterized by diminished effector and helper functions. In mammalian systems, an extensive immune regulatory network exists to limit unwanted, potentially fatal immunopathology by inducing T cell exhaustion. However, this regulatory network at times overprotects the host and fosters viral persistence by severely dampening adaptive immune responsiveness. Importantly, recent studies have shown that T cell exhaustion is mediated in part by host immunoregulatory pathways (e.g., programmed death 1 [PD-1], interleukin 10 [IL-10]) and that therapeutic blockade of these pathways either before or during persistent infection can promote viral clearance. Transforming growth factor beta (TGF-β) is another immunosuppressive cytokine known to impede both self- and tumor-specific T cells, but its role in regulating antiviral immunity is not entirely understood. In this study, we inhibited TGF-β with three potent antagonists to determine whether neutralization of this regulatory molecule is a viable approach to control a persistent viral infection. Our results revealed that these inhibitors modestly elevate the number of antiviral T cells following infection with a persistent variant of lymphocytic choriomeningitis virus (LCMV) but have no impact on viral clearance. These data suggest that therapeutic neutralization of TGF-β is not an efficacious means to promote clearance of a persistent viral infection.
Interleukin-10 (IL-10) is a broadly acting immune inhibitory cytokine that is generally thought to support tumor growth. Here we challenge this view with evidence that genetic ablation of IL-10 in the mouse significantly heightens sensitivity to chemical carcinogenesis, growth of transplanted tumors, and formation of metastases. Tumor growth in IL-10-deficient (IL-10(-/-)) mice was associated with an increased level of myeloid-derived suppressor cells (MDSC) and CD4(+)Foxp3(+) regulatory T (Treg) cells in both the tumor microenvironment and the tumor-draining lymph nodes. IL-10(-/-) MDSCs express high levels of MHC and IL-1, and they efficiently induced formation of Treg cells. IL-1 signaling blockade reduced tumor growth mediated by IL-10 deficiency, associated with a partial rescue of tumor infiltration and function of effector T cells and a decrease in tumor angiogenesis and tumor infiltration by Treg cells. Taken together, our findings establish that endogenous IL-10 inhibits inflammatory cytokine production and hampers the development of Treg cells and MDSCs, two key components of the immunosuppressive tumor microenvironment, thereby inhibiting tumor development, growth, and metastasis.
T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.
Vulvar intraepithelial neoplasia is a chronic disorder caused by high-risk types of human papillomavirus (HPV), most commonly HPV type 16 (HPV-16). Spontaneous regression occurs in less than 1.5% of patients, and the rate of recurrence after treatment is high.
We investigated the immunogenicity and efficacy of a synthetic long-peptide vaccine in women with HPV-16-positive, high-grade vulvar intraepithelial neoplasia. Twenty women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia were vaccinated three or four times with a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7 in incomplete Freund's adjuvant. The end points were clinical and HPV-16-specific T-cell responses.
The most common adverse events were local swelling in 100% of the patients and fever in 64% of the patients; none of these events exceeded grade 2 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. At 3 months after the last vaccination, 12 of 20 patients (60%; 95% confidence interval [CI], 36 to 81) had clinical responses and reported relief of symptoms. Five women had complete regression of the lesions, and HPV-16 was no longer detectable in four of them. At 12 months of follow-up, 15 of 19 patients had clinical responses (79%; 95% CI, 54 to 94), with a complete response in 9 of 19 patients (47%; 95% CI, 24 to 71). The complete-response rate was maintained at 24 months of follow-up. All patients had vaccine-induced T-cell responses, and post hoc analyses suggested that patients with a complete response at 3 months had a significantly stronger interferon-gamma-associated proliferative CD4+ T-cell response and a broad response of CD8+ interferon-gamma T cells than did patients without a complete response.
Clinical responses in women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia can be achieved by vaccination with a synthetic long-peptide vaccine against the HPV-16 oncoproteins E6 and E7. Complete responses appear to be correlated with induction of HPV-16-specific immunity.
Author Summary
West Nile virus (WNV), a mosquito-transmitted RNA virus, is a worldwide cause of severe human and animal infection. Mammalian host immune responses to WNV infection are not completely understood and a vaccine or specific therapy is unavailable for use in humans. In the present study, we investigated the putative regulatory role of interleukin-10 (IL-10) during WNV infection in mice. We found that IL-10 signaling facilitates WNV infection and suppresses antiviral cytokine production in response to viral infection. Interestingly, blockade of IL-10 signaling by IL-10 neutralizing antibody increases survival of WNV-infected mice, suggesting a potentially novel therapeutic strategy to combat WNV infection. In addition, we found that CD4+ T cells produce a significant amount of IL-10 during WNV infection, providing a more accurate cellular target for IL-10 signaling inhibition. IL-10 also plays a critical role in suppression of excessive inflammation and immunopathology caused by autoimmune diseases or host immune system responses to infections; therefore, safety and efficacy of IL-10 signaling blockade as a therapeutic strategy against WNV infection deserves consideration.
Ags characterizing tumors or chronic viral infection are generally presented to the host immune system before specific immunotherapy is initiated, and consequent generation of regulatory CD4(+) T cells can inhibit induction of desired effector CD8 T cell responses. IL-10 produced in response to ongoing Ag exposure inhibits generation of CD8 T cells in an Ag-experienced host. We now show that this IL-10 is produced by Ag experienced CD4(+) glucocorticoid-induced tumor necrosis factor receptor(+) T cells that also secrete IFN-gamma upon antigenic stimulation, that IL-10 secretion by these cells is enhanced through IFN-gamma signaling, and, unexpectedly, that IFN-gamma signaling is required for inhibition of generation of Ag-specific CD8 T cell responses in an Ag-experienced host. Systemic inhibition of both IL-10 and IFN-gamma at the time of immunization may therefore facilitate induction of effective immunotherapeutic responses against tumor specific and viral Ags.
Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection.
Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.
The mechanisms of liver hepatitis B virus (HBV)-induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice--immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8(+) T cells. Of interest, IL-17(-/-) mice phenocopied TCRδ(-/-) mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ(-/-) mice. We further observed that hepatic CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRδ(-/-) and IL-17(-/-) mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4(+) T cells. Furthermore, anti-Gr1-mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8(+) T cells and promoted HBV clearance. We also observed enhanced CD8(+) T cell number with a notable decline of MDSCs in TCRδ(-/-) mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ(-/-) mice not only exhibited increased anti-HBV CD8(+) T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8(+) T cell exhaustion.
Purpose of review:
To describe the recent data on the role of coinhibitory receptors, such as PD-1, Tim-3, CD160, as mediators of the 'exhaustion' of virus-specific CD8 T cells in chronic infections and particularly in HIV.
Recent findings:
Exhaustion of chronic virus-specific CD8 T cells is a dynamic process characterized by altered differentiation, impaired function, and compromised proliferation/survival profile of these cells. This process is mediated by coinhibitory receptors expressed on the surface of virus-specific CD8 T cells and an orchestrated function of centrally connected pathways. Coexpression of several coinhibitory receptors characterizes severely exhausted virus-specific CD8 T cells. Several studies suggest a synergistic action, instead of a redundant role, of the different receptors. In-vivo manipulation of the coinhibitory network can rejuvenate exhausted virus-specific CD8 T cell responses and constrain replication of chronic viruses, including HIV.
Summary:
Revealing the molecular basis of virus-specific CD8 T cell exhaustion in chronic infections is critical for the understanding of the disease pathogenesis and the designing of novel vaccines aiming to enhance the cytolytic arm of the immune system. This is of particular interest for the development of immunotherapies in the context of a functional cure for HIV.
Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells.
Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
Interleukin-10 (IL-10) is a multifunctional cytokine that can exert suppressive and stimulatory effects on T cells. It was investigated whether IL-10 could serve as an immunostimulant for specific CD8⁺ cytotoxic T cell (CTL) in vivo after vaccination and, if so, under what conditions. In tumor prevention models, administration of IL-10 before, or soon after, peptide-pulsed primary dendritic cell immunization resulted in immune suppression and enhanced tumor progression. Injection of IL-10, however, just after a booster vaccine significantly enhanced antitumor immunity and vaccine efficacy. Analysis of spleen cells derived from these latter animals 3 weeks after IL-10 treatment revealed that the number of CD8⁺CD44hi CD122⁺ T cells had increased and that antigen-specific proliferation in vitro was enhanced. Although cytotoxicity assays did not support differences between the various treatment groups, 2 more sensitive assays measuring antigen-specific interferon-γ production at the single-cell level demonstrated increases in the number of antigen-specific responder T cells in animals in the vaccine/IL-10 treatment group. Thus, IL-10 may maintain the number of antitumor CD8⁺ T cells. In adoptive transfer studies, the ability of IL-10 to maintain CTL function could be enhanced by the depletion of CD4⁺ T cells. This suggests that IL-10 mediates contrasting effects on both CD4⁺ and CD8⁺ T cells that result in either immune dampening or immune potentiation in situ, respectively. Appreciation of this dichotomy in IL-10 immunobiology may allow for the design of more effective cancer vaccines designed to activate and maintain specific CD8⁺ T-cell effector function in situ.
There is increasing interest in the role of T cell exhaustion and it is well known that the natural history of chronic hepatitis C virus infection (HCV) is modulated by CD8(+) T cell immunobiology. There are many pathways that alter the presence of exhaustive T cells and, in particular, they are functionally impaired by inhibitory receptors, such as programmed death-1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3). We obtained spleen, liver, and peripheral blood (before and after splenectomy) lymphoid cells from 25 patients with HCV-related cirrhosis undergoing liver transplantation for end-stage disease or splenectomy for portal hypertension. In all samples we performed an extensive phenotypic study of exhaustion markers (PD-1, Tim-3, IFNγ) and their ligands (PD-L1, PD-L2, galectin-9) in CD8(+) T cell subpopulations (both total and HCV-specific) and in antigen-presenting cells (APC; monocytes and dendritic cells). In the spleen, total and HCV-specific CD8(＋) T cells demonstrated enhanced markers of exhaustion, predominantly in the effector memory subpopulation. Similarly, splenic APC overexpressed inhibitory receptor ligands when compared to peripheral blood. Finally, when peripheral blood CD8(＋) T cells were compared before and after splenectomy, markers of exhaustion were reduced in splenic CD8(＋) T cells and APC. Our data in HCV related cirrhosis suggest that CD8(+) T cells in the spleen manifest a significantly higher exhaustion compared to peripheral blood and may thus contribute to the failure to control HCV. Counteracting this process may contribute to inducing an effective immune response to HCV.
Recently, the development of several strategies based on immunotherapy has raised hopes for a more promising way to treat cancer patients. Here, we describe how interleukin (IL)-10, a seemingly unlikely candidate, stimulates the immune system in a particularly efficacious way. IL-10, an omnipotent anti-inflammatory cytokine, delivers an equally potent immune stimulation in the context of CD8(+) T cells and tumor immunity. By activation of tumor-resident, tumor-specific CD8(+) T cells, pegylated IL-10 can induce rejection of large and metastasizing tumors in mice. Here, we summarize the mechanisms of action of IL-10, the reasons why the mechanisms may be crucial for the treatment of cancer patients, and the rationale for applying pegylated IL-10 in the clinic.
During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. We demonstrated that blockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence. Our results suggest that therapies targeting IFN-I may help control persistent virus infections.
There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
During chronic viral infections, responses by virus-specific CD8+ T cells become marginalized by the acquisition of functional defects and reduced cell numbers in a process defined as T cell exhaustion. Similarly, T cell tolerance to self-antigen is also characterized by impaired effector function and eventual deletion of self-reactive T cells. Induction of both tolerance and exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective in these distinct environments. We previously demonstrated that tolerant self-reactive CD8+ T cells expressing dual-T cell receptors (i.e., dual-TCR) could be rescued by immunization through a second TCR specific for a foreign antigen. These data revealed that T cell tolerance was regulated at the level of the self-reactive TCR. Here, dual-TCR CD8+ T cells were used to examine if exhaustion during persistent viral infection could be rescued by an analogous strategy of immunization through a second TCR not involved in recognition of virus. In direct contrast to the rescue achievable in tolerant CD8+ T cells, exhausted T cells were equally impaired through both TCR. These findings suggest that exhaustion is maintained by defects downstream of the virus-specific TCR, and establish that exhaustion and tolerance are distinctly regulated states of T cell dysfunction.
Tuberculosis remains one of the most significant human diseases of the developing world, accounting for 3,800 worldwide deaths per day. Although we currently have a vaccine for tuberculosis, BCG, this is insufficient at protecting from adult pulmonary tuberculosis in the parts of the world where a good vaccine is most needed. This has prompted the search for new vaccination strategies that can protect better than BCG, or can boost BCG-induced immunity. We discuss these subjects in line with what is known of the immune responses to BCG and Mycobacterium tuberculosis - the etiological agent of the disease, as well as the particular difficulties facing development of new vaccines against tuberculosis. A greater understanding of the factors constituting optimal protection against Mycobacterium tuberculosis infection, as well as which pathogenic factors facilitate active disease, will accelerate the delivery of safe vaccines able to restrict active tuberculosis and thus impede contagion.
Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis, but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against M. tuberculosis infection. Early production of IL-17 in the lungs following M. tuberculosis challenge of mice previously vaccinated with M. tuberculosis peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary M. tuberculosis infection, with Il10(-/-) mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated Ag-specific IFN-γ and IL-17A responses, and that this regimen gives significantly greater protection against aerogenic M. tuberculosis challenge in both susceptible and relatively resistant strains of mice. In M. tuberculosis-susceptible CBA/J mice, Ab blockade of IL-10R specifically during BCG vaccination resulted in additional protection against M. tuberculosis challenge of >1-log(10) compared with equivalent isotype-treated controls. The protection observed following BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic M. tuberculosis infection and correlated with enhanced lung Th1 and Th17 responses and increased IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2(+)CD3(-) lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting that antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis.
Type I interferon (IFN-I) promotes antiviral CD8(+)T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN-I is induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8(+)T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8(+)T cell responses. In the absence of MDA5, CD8(+)T cell responses to acute infection rely on CD4(+)T cell help, and loss of both CD4(+)T cells and MDA5 results in CD8(+)T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8(+)T cells, promoting viral clearance. Thus, effective antiviral CD8(+)T cell responses depend on the timing and magnitude of IFN-I production.
Boosting immune responses during malaria remains a challenge. Overcoming T cell exhaustion by blocking coinhibitory receptors offers a promising lead.
The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus (HCV) infection have been suggested as responsible for the poor antiviral cellular immune responses found in these patients. To overcome the immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions and concomitantly induce efficient antiviral immune responses. Two IL-10-binding peptides (p9 and p13) were selected using a phage-displayed library and their capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal transducer and activator of transcription 3) phosphorylation experiments in vitro. In cultures of human leukocytes where HCV core protein induces the production of IL-10, p13 restored the ability of plasmacytoid DC to produce interferon alpha (IFN-alpha) after Toll-like receptor 9 (TLR9) stimulation. Similarly, when myeloid DCs were stimulated with CD40L in the presence of HCV core, p9 enhanced IL-12 p
Tumor immune surveillance and cancer immunotherapies are thought to depend on the intratumoral infiltration of activated CD8(+) T cells. Intratumoral CD8(+) T cells are rare and lack activity. IL-10 is thought to contribute to the underlying immune suppressive microenvironment. Defying those expectations we demonstrate that IL-10 induces several essential mechanisms for effective antitumor immune surveillance: infiltration and activation of intratumoral tumor-specific cytotoxic CD8(+) T cells, expression of the Th1 cytokine interferon-γ (IFNγ) and granzymes in CD8(+) T cells, and intratumoral antigen presentation molecules. Consequently, tumor immune surveillance is weakened in mice deficient for IL-10 whereas transgenic overexpression of IL-10 protects mice from carcinogenesis. Treatment with pegylated IL-10 restores tumor-specific intratumoral CD8(+) T cell function and controls tumor growth.
Unlabelled:
The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus (HCV) infection have been suggested as responsible for the poor antiviral cellular immune responses found in these patients. To overcome the immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions and concomitantly induce efficient antiviral immune responses. Two IL-10-binding peptides (p9 and p13) were selected using a phage-displayed library and their capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal transducer and activator of transcription 3) phosphorylation experiments in vitro. In cultures of human leukocytes where HCV core protein induces the production of IL-10, p13 restored the ability of plasmacytoid DC to produce interferon alpha (IFN-α) after Toll-like receptor 9 (TLR9) stimulation. Similarly, when myeloid DCs were stimulated with CD40L in the presence of HCV core, p9 enhanced IL-12 production by inhibiting HCV core-induced as well as CD40L-induced IL-10. Moreover, in vitro, p13 potentiated the effect of maturation stimuli on human and murine DC, increasing their IL-12 production and stimulatory activity, which resulted in enhanced proliferation and IFN-γ production by responding T-cells. Finally, immunization with p13-treated murine DC induced stronger anti-HCV T-cell responses not only in wildtype mice but also in HCV transgenic mice and in mice transiently expressing HCV core in the liver.
Conclusion:
These results suggest that IL-10 inhibiting peptides may have important applications to enhance anti-HCV immune responses by restoring the immunostimulatory capabilities of DC.
The immune system has evolved multipronged responses that are critical to effectively defend the body from invading pathogens and to clear infection. However, the same weapons employed to eradicate infection can have caustic effects on normal bystander cells. Therefore, tight regulation is vital and the host must balance engendering correct and sufficient immune responses to pathogens while limiting errant and excessive immunopathology. To accomplish this task, a complex network of positive and negative immune signals are delivered, which in most instances successfully eliminate the pathogen. However, in response to some viral infections, immune function is rapidly suppressed leading to viral persistence. Immune suppression is a critical obstacle to the control of many persistent viral infections such as HIV, hepatitis C, and hepatitis B virus, which together affect more than 500 million individuals worldwide. Thus, the ability to therapeutically enhance immunity is a potentially powerful approach to resolve persistent infections. The host-derived cytokine IL-10 is a key player in the establishment and perpetuation of viral persistence. This chapter discusses the role of IL-10 in viral persistence and explores the exciting prospect of therapeutically blocking IL-10 to increase antiviral immunity and vaccine efficacy.
Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
In contrast to the prophylactic HPV vaccines that exhibit great promise in reducing the burden of cervical cancer, there is limited progress towards the development of immune therapeutic strategies that would help those women who are already infected with high-risk HPV and do not benefit from the current vaccines. The reason for this drawback is the lack of knowledge about the immune mechanisms that control the growth of HPV-infected or -transformed cells in vivo. It became evident that the preclinical models in rodents provide only limited information about the performance of a candidate vaccine in humans. In particular, the immune correlate for a clinical response remains to be determined. On the other hand, HPV-related malignancies provide an excellent model for cancer immune therapies in general. There is hope that the continuous efforts of academic research combined with corporate involvement will finally present an efficient product.
Interleukin 10 (IL-10) is produced by various types of human cancer, including malignant melanoma, and plays an important role in negative regulation of cell-mediated immune responses against tumors. We have developed chimeric molecules (immunoadhesins), combining the extracellular domain of human interleukin 10 receptor 1 (IL-10R1) with the Fc regions of human IgG1 heavy chain and investigated their capability of blocking the biological activities of human IL-10. Monomeric and dimeric immunoadhesins (IL-10R1/IgG1) constructs were tested for capturing human IL-10 and blocking its biological activities. Plasmid vectors that contained the IL-10 immunoadhesin constructs were directly transfected into human melanoma cell lines. Transfection of plasmid vectors into melanoma cell lines resulted in capturing of exogenously added as well as endogeneously produced IL-10. The supernatants obtained from an IL-10 non-producing melanoma cell line transfected with monomeric IL-10 immunoadhesin plasmids most efficiently captured exogenously added IL-10, compared to those obtained with the dimeric IL-10R1/IgG1 plasmid vector. Transfection of IL-10-producing melanoma cells with the monomeric IL-10 immunoadhesin plasmids totally captured endogenously produced IL-10 and enhanced T cell responses against allogeneic melanoma cells. Furthermore, purified monomeric IL-10 immunoadhesin protein showed IL-10 capturing efficacy compatible with that of IL-10-specific monoclonal antibodies. Collectively, these studies indicate that IL-10 immunoadhesins, especially in monomeric form, are potent inhibitors of biological activities of IL-10 and suggest that these molecules, alone or in conjunctions with other immunotherapeutic approaches, can be utilized for the immuno-targeting of IL-10 producing tumors.
An enormous amount of information on interleukin 10 (IL-10) has been gathered since its original description as cytokine synthesis inhibition factor (CSIF) several years ago. In this short article, Maureen Howard and Anne O'Garra summarize what is currently known of the biological properties of IL-10 and speculate on its clinical potential.
Interleukin 10 (IL-10) was discovered in 1989 by Mosmann and colleagues as an activity produced by murine type 2 helper T cells which suppressed cytokine production by type 1 helper T cells (1). This activity, initially designated cytokine synthesis inhibitor factor (CSIF), was isolated by expression cloning by Moore and colleagues (2), who subsequently identified and isolated a human analogue of CSIF by cross hybridization (3), using as their source a human helper T-cell clone produced by Roncarolo et al. (M.-G. Roncarolo and H. Spits, unpublished)
Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.
Studies of the immunology of papillomavirus infection have come of age. Synthetic virus-like particles have been validated as vaccines for several animal papillomaviruses, and have been used to map the sero-epidemiology of human papillomavirus infection and to define papillomavirus neutralizing antibodies. Induction of cell-mediated immunity to papillomavirus early proteins is poised to become a therapeutic approach to papillomavirus infection. Studies on the immune response to papillomavirus proteins in keratinocytes are shedding light on the immunological consequences of antigen presentation by epithelial cells.