Association of multispecific CD4(+) response to hepatitis C and severity of recurrence after liver transplantation

Background & Aims: After liver transplantation for hepatitis C virus (HCV), reinfection of the allograft invariably occurs. Indirect evidence suggests that the cellular immune response may play a central role. The purpose of this analysis was to determine the correlation between HCV-specific periphe ral CD4(+) T-cell responses and the severity of recurrence after liver tran splantation. Methods: Fifty-eight HCV-seropositive patients, including 43 l iver transplant recipients with at least 1 year of histological follow-up, were studied. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh heparinized blood and stimulated with either recombinant HCV antigen s (core, E2, NS3, NS4, and NS5) or control antigens. Results: Fourteen (40% ) of 35 patients with mild or no evidence of histological recurrence within their allografts responded to at least 1 of the HCV antigens. Eleven respo nded to NS3, 5 to all the nonstructural antigens, and 3 to the HCV core pol ypeptide alone. In contrast, in the 8 patients with severe HCV recurrence, no proliferation in response to; any of the HCV antigens was seen (P = 0.03 ) despite responses to the control antigens. Conclusions: Despite immunosup pression, HCV-specific, major histocompatibility complex class II-restricte d CD4(+) T-cell responses are detectable in patients with minimal histologi cal recurrence after liver transplantation. In contrast, PBMCs from patient s with severe HCV recurrence, despite being able to proliferate in response to non-HCV antigens, fail to respond to the HCV antigens. These findings s uggest that the inability to generate virus-specific T-cell responses plays a contributory role in the pathogenesis of HCV-related graft injury after liver transplantation. It is hoped that further characterization of the imm unoregulatory mechanisms related to recurrent HCV will provide the rational e for novel therapeutic strategies and diminish the incidence of inevitable graft loss.