TRANSPLANT-ASSOCIATED AUTOIMMUNE MECHANISMS IN HUMAN HEPATITIS-C VIRUS-INFECTION

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 anti gen presentation to support a hypothesis of the association of this di sease with an autoimmune pathogenesis. A greater degree of histocompat ibility match between these donors and their HCV-negative recipients w as associated with a greater predisposition to recipient HCV liver dis ease (ALT elevation) posttransplant. The HCV carrier state could be id entified 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 diseas e patients with HCV-associated cirrhosis and was insignificantly eleva ted in these patients with persistent infection in the first 2 years a fter a new liver was transplanted. There was also a moderate reduction in autologous reactivity as well as serum HCV titers among renal tran splant patients who displayed biochemical evidence of chronic liver di sease as opposed to those who did not. This appeared later in the cour se of the disease. HCV RNA could be detected in peripheral blood monon uclear 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 tran splant recipients tested. The AMLR of noninfected laboratory volunteer s could be amplified by preincubating their stimulating cells (APCs) w ith enriched HCV possibly in immune complex (pHCV-IC). This amplificat ion appeared only with specific combinations of HCV strains with HLA D R serotypes. In addition, HCV-primed T cells could be generated to the virus which displayed accelerated activation kinetics. Liver infiltra ting lymphocytes extracted from HCV-positive end-stage diseased livers had significantly higher proliferative and cytotoxic reactivity to au tologous (HCV-infected) hepatocytes than the extracted lymphocytes res ponding to autologous hepatocytes from HCV negative livers. These find ings offer evidence of dynamic autoimmune mechanisms in the spectrum o f progression of HCV disease and may help to predict the effect of int ervention at various intervals in this progression in organ transplant recipients.