Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

Kaplan, David E.; Ikeda, Fusao; Li, Yun; Nakamoto, Nobuhiro; Ganesan, Sutharsan; Valiga, Mary E.; Nunes, Frederick A.; Reddy, K. Rajender; Chang, Kyong–Mi

doi:10.1016/j.jhep.2008.01.030

Cited by 72 publications

(69 citation statements)

References 62 publications

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“…In agreement with the well-known immunomodulatory activity of IL-10 in several tissues, several studies have reported a role for IL-10 as a protective cytokine against hepatic injury in diseases such as diet-induced insulin resistance in liver (Cintra et al, 2008), experimental hepatitis induced by LPS (Santucci et al, 1996) and concanavalin A (Louis et al, 1997), schistosomiasis (Winn et al, 1998), alcoholic hepatitis (Le Moine et al, 1995), hepatitis C virus infection (Kaplan et al, 2008) and fatty liver disease (Den Boer et al, 2006). The immunosuppressive cytokine IL-10 is crucial for tolerance induction in concanavalin A-induced liver damage in mice and is mainly expressed by CD4 + CD25 + regulatory T cells (Erhardt et al, 2007).…”

Section: The Antiinflammatory Cytokine Il-10 Is Regulated By Nf-kb1 (supporting

confidence: 52%

NF‐κB in liver diseases: a target for drug therapy

Muriel

2008

J of Applied Toxicology

147

106

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There are five nuclear factor-kB (NF-kB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF-kB, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the liver. A link between inflammation and hepatocellular carcinoma through the NF-kB pathway has been observed, providing ample experimental support for the tumor-promoting function of NF-kB in various models of cancer. NF-kB has been associated with the induction of proinflammatory gene expression and has attracted interest as a target for the treatment of inflammatory disease. However, despite much attention being focused on the deleterious effects of NF-kB, activation of this factor during the resolution of inflammation is associated with the production of antiinflammatory molecules like interleukin (IL)-10 and the onset of apoptosis. This suggests that NF-kB has an antiinflammatory role in vivo involving the regulation of the resolution of inflammation. Also, NF-kB promotes liver regeneration by upregulating IL-6 and other molecules like hepatocyte growth factor. It has been postulated that the beneficial properties of NF-kB are due to p50 homodimers, whose activation prevents cholestatic and chronic liver injury. More basic understanding on the function of the diverse NF-kB factors is urgently needed in different physiological and pathological conditions, because depending on the subunit composition of the dimmer, the disease and the stage of the illness, inhibition of the factor may result in a beneficial or in a deleterious response. Copyright © 2008 John Wiley & Sons, Ltd.There are five nuclear factor-kB (NF-kB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis, and apoptosis prevention. Several inhibitors of NF-kB have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the

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Section: The Antiinflammatory Cytokine Il-10 Is Regulated By Nf-kb1 (supporting

confidence: 52%

NF‐κB in liver diseases: a target for drug therapy

Muriel

2008

J of Applied Toxicology

147

106

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“…Two skin biopsies (day 5 or 7 and day 9) and two axillary LN biopsies (weeks 1 and 2) were obtained from each monkey. Peripheral blood samples, as well as oral and genital swabs, were collected longitudinally after challenge (weekly for week 0-12, biweekly for week 12-28, monthly for week [28][29][30][31][32][33][34][35][36][37][38][39][40]. Blood samples were processed for PBMC and plasma.…”

Section: Methodsmentioning

confidence: 99%

Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity

Chang¹,

Barry

2010

Proc. Natl. Acad. Sci. U.S.A.

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Human cytomegalovirus (HCMV) and many other pathogens exploit the IL-10 pathway, as part of their infectious cycle, either through their own encoded IL-10 (hcmvIL-10 for HCMV) or manipulation of the cellular IL-10 signaling cascade. Based on the in vitro demonstrations of its pleiotropic and cell type-dependent modulatory nature, hcmvIL-10 could profoundly attenuate host immunity, facilitating the establishment and maintenance of a persistent infection in an immune-competent host. To investigate the impact of extrinsic IL-10 on the induction and maintenance of antiviral immune responses in vivo, rhesus macaques were inoculated with variants of rhesus cytomegalovirus (RhCMV) either expressing or lacking the RhCMV ortholog of hcmvIL-10 (rhcmvIL-10). The results show that rhcmvIL-10 alters the earliest host responses to viral antigens by dampening the magnitude and specificity of innate effector cells to primary RhCMV infection. In addition, there is a commensurate reduction in the quality and quantity of early and long-term, RhCMV-specific adaptive immune responses. These findings provide a mechanistic basis of how early interactions between a newly infected host and HCMV could shape the long-term virus-host balance, which may facilitate the development of new prevention and intervention strategies for HCMV. immune evasion | monkey model H uman cytomegalovirus (HCMV) establishes a lifelong persistence in immune-competent hosts in the presence of antiviral immune responses that effectively limit viral pathogenesis. The general absence of HCMV disease imposes an extraordinarily large immunological burden on its infected hosts because almost 10% of memory CD4 + and CD8 + T cells are specific to HCMV antigens (1). The ability to establish and maintain a persistent infection in the presence of such antiviral immunity requires a commensurate dedication of the HCMV coding capacity to immune evasive/modulating proteins that alter cellular activation, signaling, trafficking, and apoptosis.Up to 60% of the HCMV ORFs can be deleted without affecting viral replication in cultured fibroblasts (2). A sizeable number of these HCMV proteins subvert the immune surveillance of the hosts (3), including those that (i) disrupt natural killer (NK) cell and antigen-specific CD8 + T-cell functions, (ii) are high affinity receptors for β-chemokines and the B and T lymphocyte attenuator, (iii) modulate the cell cycle, and (iv) stimulate innate effector cell trafficking and/or alter the functionality of multiple immune cell types.

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“…In addition, Ulsenheimer [53] showed that HCV antigen-specific Tr1 and Th3 cells were detected in the peripheral blood of acute HCV patients. In another study, Kaplan et al [54] demonstrated a broad HCV-specific Tr1 response that was induced during early acute hepatitis with reduced HCV-specific CD4? T-cell proliferation and increased HCV viremia.…”

Section: Regulatory T Cellsmentioning

confidence: 98%

Different aspects of CD4 T cells that lead to viral clearance or persistence of HCV infection

Sugimoto

Shiraki

2011

Hepatol Int

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More than 170 million people worldwide are infected with hepatitis C virus (HCV). A characteristic of this virus is a high tendency toward chronic infection. Several factors affect the viral outcome after infection. Among them, HCV-specific CD4 T cells are thought to play a crucial role in controlling viremia. Cumulative data showed that spontaneously resolved individuals have vigorous CD4 T-cell responses to a broad spectrum of HCV antigens and maintain these responses over a long period of time, whereas chronically infected patients lose their CD4 T-cell responses in the acute phase of infection. Although several possibilities of why CD4 T cells lose their function have been proposed, the mechanisms are not completely understood. Moreover, there is another subset of CD4 T cells called regulatory T cells (Tregs). These cells suppress immune reaction of T cells, B cells, and antigen-presenting cells, and are thought to protect organs from immune overreaction and autoimmunity. An increasing amount of data supports the possibility that Tregs participate in the mechanism of HCV persistence. It is obvious that CD4 T cells are the main effectors controlling HCV outcome. To achieve a better prognosis, we need to understand the mechanism of how HCV earns its chronicity by escaping from host cellular immune attacks. In this review, we will focus on the role of HCV-specific T cells in controlling viremia, particularly the aspects of these cells being either inhibitors or propellers of chronic infection.

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Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

Abstract: Background & Aims-Interleukin-10 (IL-10) has been ascribed pro-viral but anti-fibrotic properties in chronic hepatitis C virus (HCV) infection. In this study, we examined the role of HCVspecific T-cell IL-10 response in patients with acute and chronic HCV infection.

Cited by 72 publications

References 62 publications

NF‐κB in liver diseases: a target for drug therapy

NF‐κB in liver diseases: a target for drug therapy

Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity

Different aspects of CD4 T cells that lead to viral clearance or persistence of HCV infection

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