EFFICACY OF IMMUNOSUPPRESSIVE DRUGS IN ISLET XENOTRANSPLANTATION - LEFLUNOMIDE IN COMBINATION WITH CYCLOSPORINE AND MYCOPHENOLATE MOFETIL PREVENTS ISLET XENOGRAFT REJECTION IN THE PIG-TO-RAT MODEL

Background. Morphological characteristics of islet xenograft rejection differ from those of islet allograft rejection. Therefore, prevention of islet xenograft rejection probably requires a different type of im munosuppression from that used in allogeneic transplantation. Methods. Fetal porcine islet-like cell clusters (ICC) were transplanted into t he renal subcapsular space of rats treated with different immunosuppre ssive protocols. The existence of a cellular infiltrate or deposits of antibodies and complement in the grafts was evaluated at different ti mes after transplantation using immunohistochemistry. Results. Treatme nt with leflunomide (LEF), cyclosporine (CsA), mycophenolate mofetil ( MMF), 15-deoxyspergualin, and rapamycin alone or in combination had an insufficient inhibitory effect on ICC xenograft rejection. However, i n animals treated with LEF+CsA, the rejection process was markedly inh ibited. However, some macrophages and T cells were still present, and at 24 days, the xenografts were destroyed. In LEF+CsA-treated animals that were given sera containing an excessive amount of rat anti-porcin e xenoreactive antibodies, marked deposits of IgG, and to some extent C3 as well, were detected along the border between intact ICC, and the xenografts were surrounded by macrophages. However, almost no cells i nfiltrated the grafts, and there were many intact ICC. In animals trea ted with LEF+CsA+MMF, only occasional infiltrating cells were seen at 12 and 24 days after transplantation, and the endocrine tissue was com pletely intact. Conclusions. LEF + CsA+MMF prevented rejection of porc ine ICC xenografts in the rat for up to 24 days after transplantation.