Patterns of immune responses evoked by allogeneic hepatocytes - Evidence for independent co-dominant roles for CD4(+) and CD8(+) T-cell responses in acute rejection

Introduction. This is the first in a series of reports that characterizes i mmune responses evoked by allogeneic hepatocytes using a functional model o f hepatocyte transplantation in mice, Methods, "Donor" hepatocytes expressing the transgene human alpha-1-antitry psin (kA1AT-FVB/N, H2(q)) were transplanted into C57BL/6 (H2(b)) or MHC II knockout (H2b) hosts treated with anti-CD4, anti-CD8, or a combination of a nti-CD4 and anti-CD8 monoclonal antibodies (mAbs), Hepatocyte rejection was determined as a loss of circulating: ELISA-detectable transgene product (h A1AT), In addition, some C57BL/6 mice underwent transplantation with FVB/N heterotopic cardiac allografts and were treated with anti-CD4 mAb, Cardiac allograft rejection was determined by palpation. Craft recipients were test ed for donor-reactive alloantibodies and donor-reactive delayed-type hypers ensitivity (DTH) responses. Results. The median survival time (MST) of allogeneic hepatocytes in normal C57BL/6 mice was 10 days (no treatment), 10 days (anti-CD4 mAb), 14 days ( anti-CD8 mAb), and 35 days (anti-CD4 and anti-CD8 mAbs), The MST of hepatoc ytes in B6 MHC class II knockout mice was 10 days (no treatment) and 21 day s (anti-CD8 mAb), The MST of cardiac allografts was 11 days (no treatment) and >100 days (anti-CD4 mAb). Donor-reactive DTH responses were readily det ected in both untreated and mAb-treated recipients. Donor-reactive alloanti body was barely detectable in untreated hosts. Conclusions. These studies demonstrate that allogeneic hepatocytes are high ly immunogenic and stimulate strong cell-mediated immune responses by both CD4(+) and CD8(+) T cells, even when treated with agents that can cause acc eptance of cardiac allografts, Indeed, CD4(+) or CD8(+) T cells seem to ind ependently cause hepatocellular allograft rejection. Allogeneic hepatocytes evoked strong donor-reactive DTH responses but were poor stimuli for donor -reactive antibody production, This is an unusual pattern of immune reactiv ity in allograft recipients.