In order to define factors which are important for the development of hepatitis C virus (HCV) infection and disease in transplant patients, we examined the role of class II MHC antigen restriction in viral antigen presentation to support a hypothesis of the association of this disease with an autoimmune pathogenesis. A greater degree of histocompatibility match between these donors and their HCV-negative recipients was associated with a greater predisposition to recipient HCV liver disease (ALT elevation) posttransplant. The HCV carrier state could be identified with significant amplification of autologous mixed lymphocyte reactivity (AMLR) in both long-term hemodialysis and long-term renal transplant patients, but the AMLR was absent in end-stage liver disease patients with HCV-associated cirrhosis and was insignificantly elevated in these patients with persistent infection in the first 2 years after a new liver was transplanted. There was also a moderate reduction in autologous reactivity as well as serum HCV titers among renal transplant patients who displayed biochemical evidence of chronic liver disease as opposed to those who did not. This appeared later in the course of the disease. HCV RNA could be detected in peripheral blood mononuclear cells (PBMC) of only a portion of HCV-infected renal transplant patients and these showed significantly higher autologous reactivity. In contrast, despite the fact that observations were earlier after de novo liver transplantation, HCV RNA (i.e., earlier in the course of a new or recurrent disease process) was found in PBMC of all liver transplant recipients tested. The AMLR of noninfected laboratory volunteers could be amplified by preincubating their stimulating cells (APCs) with enriched HCV possibly in immune complex (pHCV-IC). This amplification appeared only with specific combinations of HCV strains with HLA DR serotypes. In addition, HCV-primed T cells could be generated to the virus which displayed accelerated activation kinetics. Liver infiltrating lymphocytes extracted from HCV-positive end-stage diseased livers had significantly higher proliferative and cytotoxic reactivity to autologous (HCV-infected) hepatocytes than the extracted lymphocytes responding to autologous hepatocytes from HCV-negative livers. These findings offer evidence of dynamic autoimmune mechanisms in the spectrum of progression of HCV disease and may help to predict the effect of intervention at various intervals in this progression in organ transplant recipients.