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ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections.

ABSTRACT: Recurrent infection with human alphaherpesvirus 1 (HHV-1) may be associated with immune exhaustion that impairs virus elimination. Thymic peptides enhance immune function and thus could overcome immune exhaustion. In this study, we investigated whether reactivation of herpes infections was associated with immune exhaustion. Moreover, we examined the impact of treatment with thymostimulin on the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on T and B lymphocytes in patients suffering from recurrent HHV-1 reactivation. We also assessed the effector function of peripheral blood mononuclear cells (PBMCs) after stimulation with thymic peptides. We enrolled 50 women with reactivated HHV-1 infections and healthy volunteers. We measured the expression of various activation and exhaustion markers on the surface of PBMCs using flow cytometry. In ex vivo experiments, we measured the secretion of inflammatory cytokines by PBMCs cultured with thymostimulin. Compared with controls, patients with reactivated HHV-1 infections had increased percentages of CD3+ co-expressing CD25, an activation marker (p < 0.001). Moreover, these patients had increased percentages of CD4+ and CD8+ cells co-expressing the inhibitory markers PD-1 and PD-L1. In cultures of PBMCs from the patients, thymostimulin increased the secretion of interferon gamma (p < 0.001) and interleukin (IL)-2 (p = 0.023), but not IL-4 or IL-10.Two-month thymostimulin therapy resulted in no reactivation of HHV-1 infection during this period and the reduction of PD-1 and PD-L1 expression on the surface of T and B lymphocytes (p < 0.001). In conclusion, reactivation of herpes infection is associated with immune exhaustion, which could be reversed by treatment with thymic peptides.

SUBMITTER: Hymos A

PROVIDER: S-EPMC7178259 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections.

Hymos Anna A Grywalska Ewelina E Klatka Janusz J Klatka Maria M Korona-Głowniak Izabela I Roliński Jacek J Roliński Jacek J

International journal of molecular sciences 20200330 7

Recurrent infection with human alphaherpesvirus 1 (HHV-1) may be associated with immune exhaustion that impairs virus elimination. Thymic peptides enhance immune function and thus could overcome immune exhaustion. In this study, we investigated whether reactivation of herpes infections was associated with immune exhaustion. Moreover, we examined the impact of treatment with thymostimulin on the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on T and B lymphocytes in ...[more]

PMID: 32235584

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Project description:BackgroundDFNA5 (GSDME) belongs to Gasdermin familily that is involved in a variety of cancers and triggers cell pyroptosis after chemical treatment. However, the relationship in DFNA5 between prognosis and immune cells in diverse cancers has been receiving little attention. Tumor immune cells infiltration and exhaustion may associate with patients prognosis. The roles of DFNA5 in tumor immune cells infiltration and exhaustion have not been clarified.MethodsThe expression level of DFNA5 was determined by the Tumour Immune Estimation Resource and the Oncomine database. Then the impacts of DFNA5 in prognosis were assessed by Kaplan-Meier plotter and ULACAN. The correlations between DFNA5 and tumour-infiltrating lymphocytes were explored by TIMER. In addition, the relationships in the expression levels of DFNA5 and typical genes combination of tumour-infiltrating lymphocytes were analysed by GEPIA and TIMER. In this study, we screened the chemokine and immune related proteins interacted with DFNA5 using TurboID system to explore the instantaneous or weak interactions.ResultsDFNA5 significantly influences the prognosis in different cancers according to The Cancer Genome Atlas (TCGA). The expression levels of DFNA5 showed positive correlations to the infiltration of macrophages, CD8 + T cells, CD4 + T cells in liver hepatocellular carcinoma (LIHC), colon adenocarcinoma (COAD), and lung adenocarcinoma (LUAD). DFNA5 expression displayed obvious correlations with multiple lymphocytes gene makers in COAD, LIHC and LUAD. DFNA5 expression has effects on the prognosis of liver hepatocellular carcinoma and LUAD. DFNA5 upregulated the expression levels of PDCD1 and CD274 in a dose-dependent manner. Chemokine and immune related proteins interact with DFNA5.ConclusionsThese results indicate that DFNA5 is related to patient prognosis and immune cells, consisting of macrophages, CD4 + T cells, and CD8 + T cells, in diverse cancers. In addition, DFNA5 expression might contribute to the regulation of T cell exhaustion, tumour-associated macrophages (TAMs), and Tregs in COAD, LIHC and LUAD. DFNA5 may regulate immune infiltration via EIF2AK2. IFNGR1 was related to the functions of PD-L1 expression and PD-1 checkpoint pathway. These results indicate that DFNA5 levels may be act as a prognostic factor and predict the degrees of immune cells infiltration in LIHC and LUAD.

Project description:Background:Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to their shared routes of transmission, approximately 10% of HIV-infected patients worldwide are chronically coinfected with HBV. Additionally, liver disease has become a major cause of morbidity and mortality in HBV/HIV coinfected patients due to prolonged survival with the success of antiretroviral therapy. The relationship between immune exhaustion markers (PD-1/PD-L1) and apoptotic markers such as Fas/FasL, TGF?1, TNF-?, and Th1/Th2 cytokines are not clearly delineated in HBV/HIV coinfection. Methods:Levels of soluble Fas/FasL, TGF?1, TNF-?, and sPD-1/sPD-L1 as well as Th1 and Th2 cytokines were evaluated in the sera of HBV-monoinfected (n = 30) and HBV/HIV-coinfected (n = 15) patients and compared to levels in healthy controls (n = 20). Results:HBV-monoinfected patients had significantly lower levels of the anti-inflammatory cytokine IL-4 (P < 0.05) and higher levels of apoptotic markers sFas, sFasL, and TGF?-1 (P < 0.001) compared to healthy controls. Coinfection with HIV was associated with higher levels of sFas, TNF-?, and sPD-L1 (P < 0.005), and higher levels of the pro-inflammatory cytokines IL-6, IL-8, and IL-12p70 (P < 0.05) compared to healthy controls. Patients with HBV infection had a unique biomarker clustering profile comprised of IFN-?, IL12p70, IL-10, IL-6, and TNF-? that was distinct from the profile of the healthy controls, and the unique HIV/HBV profile comprised GM-CSF, IL-4, IL-2, IFN-?, IL12p70, IL-7, IL-10, and IL-1?. In HBV monoinfection a significant correlation between sFasL and PD1(r = 0.46, P = < 0.05) and between sFas and PDL1 (r = 0.48, P = <0.01) was observed. Conclusion:HBV-infected and HBV/HIV-coinfected patients have unique apoptosis and inflammatory biomarker profiles that distinguish them from each other and healthy controls. The utilization of those unique biomarker profiles for monitoring disease progression or identifying individuals who may benefit from novel immunotherapies such as anti-PD-L1 or anti-PD-1 checkpoint inhibitors appears promising and warrants further investigation.

Dataset Information

ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections.

Publications

ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections.

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