HCV-Induced Immune Responses Influence the Development of Operational Tolerance After Liver Transplantation in Humans

Abstract

Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8(+) T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.

Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen

“…A similar mechanism may be driven by CMV infection after LTx, which also causes inflammation in the graft and in other organs (52), whereas CMV is able to induce IFN-a production (56). A possible relationship between inflammation and reduced alloresponses after LTx is supported by a recent study that showed that chronic HCV patients who are operationally tolerant after LTx overexpress type I IFN and IFN-stimulated genes in the liver graft (57). A second possible explanation for the association between CMV infection and CD8 + T cell hyporesponsiveness is that CMV produces viral IL-10 (58), which inhibits the expansion of alloreactive CD8 + T cells.…”

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

“…Interestingly, HCV infection does not negatively influence the establishment of operational tolerance of the liver allograft after the withdrawal of immunosuppression, whereas concomitant infections are generally considered to be detrimental to the process of allograft tolerance [62]. As expected, the induction of Treg might be involved in this phenomenon, alongside high levels of intrahepatic interferon-stimulated gene expression which may paradoxically promote a tolerogenic micro-environment in the context of HCV infection.…”

Infectious Diseases in Transplantation—Report of the 20th Nantes Actualités Transplantation Meeting

“…18,19 Based on these experimental observations, Alberto Sanchez-Fueyo and co-workers (London, UK) have demonstrated that persistent hepatitis C virus (HCV) infections exert clinical immunoregulatory effects that alleviate deleterious alloimmune responses. 20 This original work challenges the notion that heterologous immunity and inflammatory responses within the transplant will necessarily prevent tolerance.…”