THE REJECTION MECHANISM OF RAT PANCREATICODUODENAL ALLOGRAFTS WITH A CLASS-I MHC DISPARITY

The present study has demonstrated for the first time that PVG.R1 (RT1.A(a)B(c)D(c)C(c)) pancreatic grafts are rejected by so-called ''low''-responder PVG (RT1.A(c)B(c)D(c)C(c)) recipients with an isolated class I MHC disparity (mean survival time; MST: 21.4+/-1.8 days, n=5), whereas PVG.R1 heart grafts are able to survive indefinitely (MST:>100 days, n=S). Splenic CD4(+) T cells but not CD8(+) T cells from the PVG recipients of PVG.R1 pancreatic grafts show a remarkable proliferative response against donor class I RT1.A(a) alloantigens, while only a minimal proliferation is observed in the PVG recipients of PVG.R1 heart grafts or naive PVG rats. Naive PVG rats display an extremely low frequency of IL-8-producing helper T cell precursors (fThp) of 1/40,609+/-15,441 against class I RT1.A(a) alloantigen. The PVG recipients of PVG.R1 heart grafts have a slightly greater fThp of 1/17,326+/-6822. On the other hand, the PVG recipients that rejected PVG.R1 pancreatic grafts show a significantly increased fThp of 1/5030+/-3396 compared with those of PVG.R1 heart grafts (P<0.05) or naive PVG rats (P<0.01). The fre quency of cytotoxic T cell precursors (fTcp) increases slightly in the PVG recipients of PVG.R1 pancreatic grafts (1/1848+/-330) compared with those of PVG.R1 heart grafts (1/2215+/-2131) or naive PVG rats (1/2476+/-585). The size of cytotoxic T cell clones alone does not adequately account fora proliferation sufficient to complete the rejection of pancreatic grafts. The PVG recipients of PVG.R1 pancreatic grafts, but not heart grafts, demonstrate a strong cytotoxic alloantibody response to donor class I RT1.A(a) alloantigens. In the study of alloantibodies, IgM is detected mainly in the early phase and IgG in the late phase during the course of pancreatic rejection. It is determined that in blocking studies by FACS analysis these antibodies target class I MHC antigens. These results suggest that cytotoxic T cells do not appear to be responsible for the rejection of PVG.R1 pancreatic grafts in PVG recipients. Rather, the rejection is mediated by CD4(+) T cells and complement-fixing antibodies directed at class I MHC antigens.