Evidence in rodents suggests that islet pretreatment to reduce islet immunogenicity will also require some form of immunosuppression of the recipient for islet allograft acceptance in highly reactive donor-recipient pairs. We attempted to ascertain whether outbred dogs would also require treatment of both donor islets and the recipient to prolong islet allograft survival. Untreated canine islets are uniformly rejected in 6-10 days in beagles. Tissue culture alone, at 37°C for 7 days, or treatment of freshly prepared islets with antila monoclonal antibodies (MoAbs) (B1F6 + 7.2) did not prolong canine islet allograft survival. Treatment of culture-maintained canine islets with anti-la MoAbs plus complement resulted in prolongation of islet allograft survival for 188 and 368 days in two of seven pancreatectomized nonimmunosuppressed beagles. The administration of low doses of cyclosporin A (CsA) intramuscularly, to recipients of untreated canine islet allografts had no effect on graft survival. By contrast, six of nine CsA-treated recipients of islets that were also treated with anti-la MoAbs (B1F6 + 7.2) plus complement showed prolongation of graft survival. Euglycemia was sustained for 19, 34, 89, and 300 days after the CsA was discontinued (day 30) in four of these animals. Two animals had unstable grafts from the beginning that failed 23 and 29 days after transplantation. Our results indicate that simple maneuvers like short-term tissue culture at 37°C and treatment of freshly isolated islets with anti-la MoAbs and complement are inadequate to prevent rejection in outbred pancreatectomized beagles. In contrast, low-dosage CsA acts synergistically with the in vitro treatment of islets with anti-la MoAbs to prolong islet allograft survival in outbred dogs with induced diabetes mellitus.

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