Mechanisms of Tolerance: Role of the Thymus and Persistence of Antigen in Calcineurin-Induced Tolerance of Renal Allografts in MGH Miniature Swine

The induction of donor-specific tolerance remains a major goal of clinical transplantation. Partially inbred MGH miniature swine, in which swine leukocyte antigens (SLA) have been defined and fixed, have been utilized extensively as a preclinical model for tolerance induction. This preclinical large-animal model is an invaluable tool for studying the mechanism of transplantation tolerance. Recently, we have investigated the role of the persistence of donor antigen in the maintenance of tolerance and the peripheral regulatory cells’ ability to confer tolerance to naïve animals. Mechanisms of tolerance can be elucidated in part by attempting to interfere with (or “break”) the tolerant state. We have previously reported that a short course of calineurin inhibition permits the uniform development of long-term, donor-specific tolerance to renal allografts in juvenile miniature swine. Once tolerant, animals that undergo graft nephrectomy and immediate retransplantation accept donor-MHC matched kidneys while maintaining stable renal function without further immunosuppression. Utilizing this model we have attempted to break tolerance using several strategies. These have included administration of recombinant IL-2 to provide additional T-cell help, manipulation of the host thymus, and removal of donor grafts. Our data indicate that (1) presence of an intact thymus is essential for the induction, but not for the maintenance of tolerance; (2) the persistence of the donor renal graft is essential for the indefinite continuation of tolerance; and (3) the pathway of donor antigen presentation, in tolerant and previously tolerant animals, is important for preservation or loss of the tolerant state. Although obvious limitations exist with regard to animal studies, our consistently reproducible results using MHC inbred miniature swine provide a unique opportunity to study the mechanisms of transplantation in animals physiologically similar to humans. As we have previously shown, our results are highly suggestive of what will occur in clinical human transplantation protocols.