Transplant-associated autoimmune mechanisms in human hepatitis C virus infection

Abstract

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.

The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients.

“…First, indicative of altered responses to nominal peptides presented by autologous antigen presenting cells in the DBMC group as we have previously described in hepatitis C virus-infected recipients (12), in the present case possibly cytomegalovirus (despite depressed humoral immunity), which also appeared to be more clinically detectable in the bone marrow-infused group (not shown). Second, indicative of a small number of donor chimeric cells in recipient peripheral blood stimulating the recipient T cells by either direct or indirect alloantigen presentation.…”

“…In previous reports, we have depicted the autologous mixed lymphocyte reaction, an in vitro proliferative response of purified T cells versus autologous NT cells (i.e., purified B cells and antigen presenting cells), as a screening assay of immune autoregulation, altered because of viral infections (11) or other events indicative of aberrant T cell reactivity against self-MHC class II molecules (or their nominal peptides) presented by antigen presenting cells (12). Thus far, the changes seen in the AMLR assays occurring between 6 and 14 mo posttransplant when compared with those obtained pretransplant have indicated a trend towards an increase in response in the DBMC group compared with preoperative reactivity (Fig.…”