Primary nonfunction of islet xenografts in rat recipients results from non-t-cell-mediated immune responses

Abstract

Primary nonfunction (PNF) and early graft failure affect the functional mass of islet tissue engrafted, and represent a major problem in clinical islet transplantation. Previous studies have shown that grafts of isolated canine pancreatic islets survive and function in immunocompetent murine recipients until graft rejection. In contrast, a very high rate of PNF has been demonstrated in rat recipients of canine islet xenografts.l Routine immunosuppressive protocols, such as cyclosporin therapy, have little effect on prolongation of graft survival in this combination. A better understanding of the mechanisms involved in this strong, rapid immune response in the rat may provide focus in the development of strategies of immunosuppression which would be clinically relevant. To identify the effector mechanism of PNF in the dog-to-rat islet transplant model, we have shown that long-term culture, or inhibition of native complement, slightly improves early islet function in this model. In this study, we further investigate the effect of inhibiting lymphocyte activity, nitric oxide (NO) production, or macrophage (M(p) function on canine islet xenograft survival in rat recipients.