Characterization of HCV-Specific CD4+Th17 Immunity in Recurrent Hepatitis C–Induced Liver Allograft Fibrosis

Basha, Haseeb Ilias; Subramanian, Vijay; Seetharam, Anil; Nath, Dilip S.; Ramachandran, S.; Anderson, Christopher; Shenoy, Surendra; Chapman, William C.; Crippin, Jeffrey S.; Mohanakumar, Thalachallour

doi:10.1111/j.1600-6143.2011.03458.x

Cited by 32 publications

(36 citation statements)

References 35 publications

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“…The immune response to HCV is a critical determinant of allograft fibrosis and a predominant Th2 (13, 14, 37) and Th17 (15) immunity is associated with increased fibrosis and poor outcome. Cytokines including IL-1β, IL-6 and IL-8 have been shown to promote fibrosis (38–41).…”

Section: Discussionmentioning

confidence: 99%

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Donor Graft Steatosis Influences Immunity to Hepatitis C Virus and Allograft Outcome After Liver Transplantation

et al. 2011

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Background Hepatitis C (HCV) recurrence following orthotopic liver transplantation (OLT) is universal, often with accelerated allograft fibrosis. Donor liver steatosis is frequently encountered and often associated with poor early post-operative outcome. The study’s aim was to test the hypothesis that allograft steatosis alters immune responses to HCV and self-antigens promoting allograft fibrosis. Methods Forty-eight HCV OLT recipients (OLTr) were enrolled and classified based on amount of allograft macrovesicular steatosis at time of OLT. Group 1-No Steatosis (0–5% steatosis, n=21), Group 2 – Mild (5–35% - n=16), Group 3 – moderate (>35%, n=11). Cells secreting IL-17, IL-10, IFN-γ in response to HCV antigens were enumerated by ELISpot. Serum cytokines were measured by Luminex, antibodies (Abs) to Collagen (Col) I, II, III, IV, V by ELISA. Results OLTr of moderate steatotic grafts had the highest incidence of advanced fibrosis in protocol one-year post-OLT biopsy (10.8% vs. 15.8% vs. 36.6%, r = 0.157, p<0.05). OLTr from Groups 2 and 3 had increased HCV specific IL-17 (p<0.05) and IL-10 (p<0.05) with reduced IFN-γ (p<0.05) secreting cells when compared to group 1. This was associated with increase in serum IL-17, IL-10, IL-1β, IL-6, IL-5 and decreased IFN-γ. In addition, there was development of Abs to Col I, II, III and V in OLTr with increased steatosis (p<0.05). Conclusion The results demonstrate that allograft steatosis influences post-OLT HCV specific immune responses leading to a IL-17 T-helper response and activation of humoral immune responses to liver associated self antigens which may contribute to allograft fibrosis and poor outcome.

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Section: Discussionmentioning

confidence: 99%

“…Immunological factors including T-cell responses to HCV (12–15), immunity to extracellular matrix (ECM) antigens (Collagens [Col]) (16) have been implicated in progression of allograft fibrosis. Donor factors including graft quality can influence HCV recurrence (17).…”

Section: Introductionmentioning

confidence: 99%

Donor Graft Steatosis Influences Immunity to Hepatitis C Virus and Allograft Outcome After Liver Transplantation

et al. 2011

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“…We have previously identified differential regulation of inflammatory cytokines, such as IL-17, IL-1␤, IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), gamma interferon (IFN-␥), IL-4, IL-5, IL-10, and YKL40 in HCV patients with fibrosis (23,27). In this study, we demonstrate that HCV-mediated specific regulation of miRNA-449a and miRNA-107 alters expression of CCL2, a major inflammatory chemokine that is regulated by the IL-6R complex components IL-6R and JAK1.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Sarma

Tiriveedhi

Crippin

et al. 2014

J Virol

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Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBP␣, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBP␣, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBP␣. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis. IMPORTANCEHepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.

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“…Moreover, Treg may actively participate in the acceleration of fibrosis in this particular context [57]. This is an important issue because Treg have a positive effect on graft tolerance, and strategies consisting of raising their levels in order to reduce or even discontinue immunosuppressive therapy are currently being investigated.…”

Section: Open Issues and Future Perspectivesmentioning

confidence: 99%

“…When Treg were analyzed during a recurrence of HCV fibrosis at least 1 year post-transplantation, severe fibrosis was associated with high levels of peripheral CD4+ CD25+ FoxP3+ Treg, high levels of IL10-secreting CD4+ T-cells and high levels of Th17 [57]. Treg inhibited the production of IFN gamma from HCV-specific CD4+ T-cells but not the production of IL17, suggesting that Treg may suppress the immune response against HCV while allowing the establishment of a pro-inflammatory environment.…”

Section: Treg and Hcv Recurrence After Liver Transplantationmentioning

confidence: 99%

Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence

Barjon

Dahlqvist

Calmus

et al. 2015

Digestive and Liver Disease

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Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.

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Characterization of HCV-Specific CD4+Th17 Immunity in Recurrent Hepatitis C–Induced Liver Allograft Fibrosis

Cited by 32 publications

References 35 publications

Donor Graft Steatosis Influences Immunity to Hepatitis C Virus and Allograft Outcome After Liver Transplantation

Donor Graft Steatosis Influences Immunity to Hepatitis C Virus and Allograft Outcome After Liver Transplantation

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence

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