Prolongation of Islet Xenograft Survival (Rat to Mouse)

Abstract

The portal vein technique was modified to permit transplantation of isolated islets via the portal vein into diabetic mice. Transplants of BALB/c islets, via the portal vein, into diabetic BALB/c mice maintained normoglycemia for > 200 days. Morphologic studies of the liver of the recipients at 203–210 days revealed intact islets with a normal degree of beta granulation. A marked prolongation of islet xenograft survival was obtained by maintaining isolated rat islets (Wistar-Furth) in vitro at 24°C for 7 days, transplanting the islets into diabetic recipients (BALB/c) via the portal vein, and administering one i.v. injection of antiserum to mouse and rat lymphocytes at the time of transplantation. Seventy percent of the recipients were normoglycemic at 100 days and 33% were normoglycemic at 200 days after transplantation. Omitting the single injection of rat antilymphocyte serum from this protocol and using only mouse antilymphocyte serum and 1 wk of culture (24°C) resulted in a 10% survival of the islet xenografts at 100 and 200 days after transplantation. Morphologic studies on normoglycemic recipients (BALB/c) from 63 to 200 days after transplantation of rat islets revealed normal islets in the livers of the recipients with focal aggregates of lymphoid cells adjacent to the islets. The mechanism for induction of these lymphoid aggregates is unknown. Regardless of the mechanism of induction, the lymphoid aggregates did not interfere with the function of the islet transplants since the recipients were normoglycemic. Rejection of an established islet xenograft of rat islets was induced by the i.v. injection of 107 rat spleen cells into the recipient 57 days after transplantation. The mechanisms involved in obtaining marked prolongation of islet xenograft survival without the continuous use of immunosuppressive agents are not clearly established. The simplest explanation of the findings is that the pretreatment regimens destroyed or altered passenger lymphoid cells which are required for the induction of immune rejection of the islet xenografts by the recipient.