Effect of liver transplantation on islet allografts - Up-regulation of fasligand and apoptosis of T lymphocytes are associated with islet graft tolerance

Background. Liver allografts in spontaneously tolerant strain combinations can protect other organs of the same donor origin from rejection and revers e ongoing rejection in previously placed grafts. The aims of this study wer e to examine whether liver allografts have the same protective effect on is let allografts and to investigate the underlying mechanisms. Methods. PVG islets were transplanted beneath the kidney capsule of strepto zotocin-induced diabetic DA rats with or without liver allografting, The ce llular infiltrate, and the extent of apoptosis and of Fas ligand (FasL) exp ression in the islet grafts were evaluated on days 2, 4, and 7 after transp lantation by means of immunostaining and the in situ terminal deoxynucleoti de transferase-mediated dUTP nick end labeling assay. Donor and recipient m ixed lymphocyte reactions (MLR) were determined at 7 days or 100 days after islet transplantation. Results. Islet allografts transplanted alone were rapidly rejected within 5 -8 days. Rejection was delayed, but not prevented, when islets were transpl anted simultaneously with the Liver. Liver transplantation 1 month before i slet transplantation resulted in longterm survival (>100 days) of islet gra fts in three of seven animals, whereas the other four died of liver rejecti on with functional islet grafts. Liver transplantation on day 4 after islet grafting reversed ongoing islet rejection and led to indefinite islet graf t survival in three of seven cases. There was a progressive increase of cel lular infiltration in all of the islet allografts, but the intensity of the infiltrate did not correlate with the outcome of the islet allografts. Isl et rejection was characterized by an early dominance of monocytes/macrophag es and CD25(+) T cells in the infiltrates, a high incidence of apoptotic be ta cells in grafts, and a sensitized status in the MLR. Tolerance of islet allografts was associated with increased numbers of dendritic cells in the graft infiltrates, up-regulation of FasL, and prominent apoptosis of allore active leukocytes in the islet grafts, as well as donor-specific MLR suppre ssion in long-term survivors. Conclusions. These results demonstrate that the extent of the protective ef fect of liver transplantation on islet allografts varies with the time of l iver grafting, ranging from delay in islet rejection to complete islet acce ptance. Islet graft tolerance induced by liver transplantation is the resul t of an immune process that involves up-regulation of Fas ligand expression on, and apoptosis of, islet graft infiltrating lymphocytes.