Inbred miniature swine provide a unique preclinical model for the study oftransplantation immunity andtolerance. Overthe past 18 years, we have utilized this model to study a robust form oftolerance of MHC class I-mismatched renal allografts that is routinely achieved following a short course of calcineurin inhibitors. Thisproposal represents a G37 renewal ofthe previous long-standing ROl, which received a Merit Award at the timeofthe last competitive renewal. During the past three and one-half years since that renewal, we have madesignificant progress in understanding the role of regulatory T cells (T-reg) in determining the balance betweenalloreactivity and down-regulation of immune reactivity to tolerated renal allografts. Among these studies, hasbeen an evaluation ofthe possible role ofantigen presentation through direct or indirect pathways of activationin the reinforcing oftolerance by donor-type skin allografts in previously tolerant animals from which thetolerizing graft has been removed. We have obtained considerable evidence for dominance of down-regulationby the.direct pathway in this phenomenon. In the next project period, we intend to: 1) Complete our studies onthe nature of cell populations responsible for adoptive transfer oftolerance that are still in progress; 2)Determine whether the thymus is required for breaking and/or reinforcing tolerance after graftectomy inanimals tolerant of class I mismatched renal allografts; and 3) Examine the mechanism by which B cell immunityto class I antigens is controlled in animals tolerant ofa class I-mismatched renal allograft through evaluation ofthe influence of tolerance on antibody fine specificity. The broader goal ofthese studies remains to develop anunderstanding ofthe mechanisms by which allograft tolerance is induced and maintained in this large-animalmodel, in order to permit development of appropriate protocols for induction oftolerance to organ allografts inthe clinic.
Immune tolerance of transplanted organs would allow patients to avoid long-term immunosuppressive drugsand the complications caused by these drugs. We have developed a large animal model in which toleranceof kidney transplants can be induced reproducibly. Our goal here is to understand the mechanism oftolerance in this model in order to eventually extend the studies to human organ transplants.
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