PROLONGATION OF PIG ISLET XENOGRAFT SURVIVAL IN RATS IMMUNOSUPPRESSEDWITH FK506

FK506 a new and potent immunosuppressive agent has been shown to be ef fective in prolonging pancreatic islet allograft survival. The present study was to determine its efficacy in prolonging pig islet xenotrans plantation in two different strains of rat recipients. A total of two dosages of FK506 at 1 or 2 mg/kg per day for 2 weeks and then at weekl y intervals were tested as monotherapy for their effect on the surviva l of renal subcapsular xenografts of purified or impure adult pig isle ts in inbred ACI and outbred Wistar rats. Histological assessment indi cated that FK506 at 2 mg/kg per day significantly prolonged purified p ig islet xenograft survival and to 7.5 months in two of three ACI reci pients. Monotherapy with a lower dosage of FK506 or transplantation wi th impure pig islets resulted in increased graft survival time over co ntrols, but less than that with the 2 mg/kg per day FK506. The viable pig islet xenografts showed a normal appearance and were readily ident ified by immunohistochemical staining for insulin and glucagon and fur ther confirmed by immunohistochemical staining with anti-pig islet spe cific monoclonal antibody clone P44, developed in our laboratory. Mono nuclear cell infiltration, mainly of the CDS-positive T-cell subset, i ncreased with the duration of the graft in the recipient. By 7.5 month s the majority of the xenografted islet cells were enclosed by the cel lular infiltrate. The in vitro perfusion study of pig islets that had survived for 1 or 2 months in vivo showed that they were responsive to glucose stimulation with increase in insulin secretion into the perfu sate. The results demonstrated that FK506 significantly prolonged pig islet survival in two rat strains and suggested that it is an effectiv e immunosuppressant for the xenotransplantation model. (C) 1997 Elsevi er Science Ireland Ltd.