Search

Regulatory T cells (Treg) are important inhibitory immune cells to establish immune tolerance, which play a pivotal role in regulating excessive immune response and autoimmune diseases of the host. Previous studies related to transplant immune tolerance have confirmed that increasing the number of Treg in vivo or enhancing the function of Treg serve as a therapeutic strategy to induce transplant immune tolerance. At present, Treg-based induction methods for transplant immune tolerance include adoptive infusion of Treg, in vivo amplification of Treg and utilization of antigen)specific Treg. In this article, the characteristics and mechanism of Treg, the latest research progress on basic experiments and clinical practice of Treg related to transplant immune tolerance at home and abroad were reviewed, and future challenges and development of Treg therapy were prospected, aiming to unravel the significance and application prospect of Treg in transplant immune tolerance, explore the advantages and limitations of Treg therapeutic strategies, and provide reference and evidence for subsequent research in this field. [ABSTRACT FROM AUTHOR]

Abstract Background The results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies. Methods The authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis. Results The pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients with liver cancer and controls, and for rs733618 polymorphism among patients with colorectal cancer and controls in pooled meta-analyses. Conclusions This meta-analysis suggested that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer.

Small cell lung cancer (SCLC) is a malignant solid tumor. In recent years, although immune check point inhibitors (ICIs) have achieved important advances in the treatment of SCLC, immune-related adverse events (irAEs) have occurred at the same time during the therapeutic period. Some irAEs lead to dose reduction or treatment rejection. The immune microenvironment of SCLC is complicated, therefore, understanding irAEs associated with ICIs is of great importance and necessity for the clinical management of SCLC. However, the lack of comprehensive understanding of irAEs in patients with SCLC remains remarkable. This review aims to provide an up-to-date overview of ICIs and their associated irAEs in patients with SCLC based on present clinical data.

Small cell lung cancer (SCLC) is a malignant solid tumor. In recent years, although immune check point inhibitors (ICIs) have achieved important advances in the treatment of SCLC, immune-related adverse events (irAEs) have occurred at the same time during the therapeutic period. Some irAEs lead to dose reduction or treatment rejection. The immune microenvironment of SCLC is complicated, therefore, understanding irAEs associated with ICIs is of great importance and necessity for the clinical management of SCLC. However, the lack of comprehensive understanding of irAEs in patients with SCLC remains remarkable. This review aims to provide an up-to-date overview of ICIs and their associated irAEs in patients with SCLC based on present clinical data. [ABSTRACT FROM AUTHOR]

Background: The results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies. Methods: The authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis. Results: The pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients with liver cancer and controls, and for rs733618 polymorphism among patients with colorectal cancer and controls in pooled meta-analyses. Conclusions: This meta-analysis suggested that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer. [ABSTRACT FROM AUTHOR]

Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others. [ABSTRACT FROM AUTHOR]

The essential role played by CD25+CD4+ regulatory T cells (TR cells) in the control of physiological as well as pathological immunity is now well established, but many aspects of their biology still remain unclear. One of the unresolved issues regards their development: where does this occur, what signals are required, and how do TR cells fit into the larger taxonomy of the T-cell family? Recent data has begun to shed light on the development and function of these important cells. [Copyright &y& Elsevier]

SUMMARY Kawasaki disease (KD) is an acute febrile illness of early childhood caused by vasculitis. Whether or not peripheral blood T cells are activated in acute KD remains uncertain, as some reports have presented evidence of peripheral blood T cell activation, whereas others suggest that the level of peripheral blood T cell activation is low during acute KD. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) is a surface molecule of activated T cells. We therefore investigated intracellular CTLA-4 expression in the peripheral blood T cells of patients with acute KD as a marker of T cell activation. We collected blood samples from 20 patients with KD and six with Epstein–Barr virus infectious mononucleosis (EBV-IM) who were admitted to our hospital, as well as 13 healthy children. We determined the intracellular expression of CTLA-4 in T cells by flow cytometry. We demonstrated that the intracellular expression of CTLA-4 is up-regulated in peripheral blood CD3+ T cells, CD4+ T cells and CD8+ T cells at the early part of the acute stage in KD. However, the mean percentages of intracellular T cells expressing CTLA-4 in EBV-IM patients were about fourfold higher than those in T cells from patients with acute KD. Our results suggested that the level of activation of peripheral blood T cells is very low during acute KD. [ABSTRACT FROM AUTHOR]

• Factors influencing tumor responders treated with ICIs. • Predictive biomarkers of irAEs. • New potential mechanisms of resistance to ICI therapy. Cancer immunotherapy has brought a great revolution in the treatment of advanced human cancer. Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have been widely administrated in the past years and demonstrated promising in a variety of malignancies. While some patients show benefit from ICIs, others do not respond or even develop resistance to these therapies. Among the responders, the treatments are consequently accompanied with immune-related adverse effects (irAEs), which are diverse in their effected organs, degree of severity and timing. Some of the toxicities are fatal and result in discontinuance of immunotherapy. The toxicity profile from anti-CTLA-4 to anti-PD-1/PD-L1 immunotherapies is distinct from those caused by conventional anticancer therapies, though their presentation may be similar. In order to better help clinicians recognize, monitor and manage irAEs in a growing population of cancer patients who are receiving ICI therapy, this article summarizes the FDA approved ICIs and focuses on (1) existing toxic evidence related to ICIs, (2) occurrence of irAEs, (3) factors influencing tumor responders treated with ICIs, (4) predictive biomarkers of irAEs, and (5) new potential mechanisms of resistance to ICI therapy. [ABSTRACT FROM AUTHOR]

In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Usingex vivoisolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression. [ABSTRACT FROM AUTHOR]

Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others., Competing Interests: The authors declare no conflict of interest.

In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4+regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I–IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p= 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p= 0.009), relative lymphopenia (p= 0.036), and a higher mDC/pDC ratio (p= 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increasedCTLA-4expression by Tregs (p= 0.005) and MDSC levels (p= 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ T-cells andCTLA-4expression in Tregs conferred a negative prognosis, indicating theirin vivorelevance. Remarkably, circulatingCTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDO+ PBMCs. We conclude that the expression of IDO, PD-L1, andCTLA-4in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response. [ABSTRACT FROM PUBLISHER]

Background: Sublingual administration of Phleum pratense allergen immunotherapy (SLIT) tablets is a clinically efficient treatment for grass pollen–induced rhinoconjunctivitis. This immunotherapy downregulates TH2 immune responses, induces tolerogenic pathways, and increases regulatory T cells. However, associated immune response markers of allergen desensitization remain undefined. Objective: We sought to characterize the kinetics of individual changes in the immunologic response to grass tablet SLIT. Methods: We evaluated the systemic effects of SLIT in a longitudinal analysis of humoral and cellular immune parameters in peripheral blood samples. Results: Grass tablet SLIT administration induced a 2-phase systemic humoral and cellular response. The TH2 response was initially exacerbated and detected as increased allergen-specific IgE (sIgE) and IgG4 (sIgG4) levels and an increase in IL-4–producing cells, followed by downregulation of the TH2 response with a shift toward a TH1 cytokine profile. T cells with a regulatory phenotype were also elicited. Statistical correlations between immunologic measurements for each patient throughout therapy indicated that TH2 response downregulation and reduction of the immediate SLIT-induced IgE response were associated with increased allergen-specific IgG4 synthesis early in therapy. TH2 response downregulation by month 4 correlated with increased frequency of CD4+ T cells with a regulatory phenotype by 12 months. Conclusion: Changes in sIgE levels after therapy were linked to a specific IgG4 response, and production of blocking antibodies correlated with TH2 response downregulation. Reduced IL-4+ cell frequency was linked to an increase in the frequency of CD4+ T cells with a regulatory phenotype. Changes in sIgE levels and reduced IL-4 and blocking antibody levels could thus be used as indicators of a patient's immune response to therapy. [Copyright &y& Elsevier]