The only therapy available for end stage organ failure is organ transplantation. Without immunosuppressive drugs the transplanted organ would be rejected within days of transplantation. Current therapies have shown an enormous improvement in transplant survival over the last two decades. However, these therapies result in non-specific suppression of the immune system leaving the patient open to opportunistic infection and under an increased risk of developing cancer. Clearly, new therapies that result in specific suppression of only the graft-specific response for the lifetime of the recipient are acutely needed. In murine models of transplantation CD4- and CD8-specific monoclonal antibody treatment given at the time of grafting can prevent graft rejection. Tolerance is graft antigen-specific and induces CD4+ regulatory cells that are capable of preventing (suppressing) non-tolerant cells from responding to graft antigens but only if the tolerant and non-tolerant cells see their respective antigens on the same graft. This is termed "suppression by linked recognition". In this application we hope to develop a model of pre-transplant tolerance induction to a non-transplantation antigen to promote tolerance to a transplant by linked recognition. Using a murine model of islet transplantation we propose to induce antigen-specific tolerance to ovalbumin (OVA) with non-depleting CD4- and CD8-specific monoclonal antibodies (mAb). When tolerance to OVA is established we will test the ability of OVA-induced suppressor cells to suppress a transplantation antigen-specific response by grafting with an islet allograft that does or does not express OVA under the control of the rat insulin promoter. We will further challenge this system by testing its ability to induce islet transplantation tolerance in diabetic mice. In the course of these studies we hope to develop a new therapeutic strategy ultimately aimed to prevent transplantation.