Regulatory mechanisms in transplantation tolerance: the induction of tolerance by adoptive transfer in MHC-inbred miniature swine
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Organ transplantation has been the standard of care for end-stage organ failure. While one-year renal allograft survival has increased to over 90% in the past couple of decades with the use of new immunosuppressants, the long term survival of kidney allografts have remained the same due to unchanged rate of chronic rejection. Even with acceptance of renal allografts, patients require lifelong use of immunosuppressants. The induction of transplantation tolerance may allow for patients to receive transplants without having to deal with the side effects of immunosuppression. Using a unique miniature swine model, we have demonstrated uniform induction of tolerance in recipients of MHC class-I mismatched renal allografts with 12 days of high Cyclosporine A. Transplantation tolerance in this model is induced and maintained by regulatory T cells. In our study, we used this model to attempt to induce tolerance in naïve recipients through adoptive transfer of donor primed or unprimed peripheral regulatory cells and/or kidneys from long-term tolerant donor-matched swine. SLAdd miniature swine received 150 rads of whole body irradiation and class I-mismatched SLAgg kidneys from naive pigs with or without co-transplanted kidneys and/or cells from long-term tolerant SLAdd recipients of SLAgg kidneys. Naive kidneys transplanted without a long-term tolerant kidney were acutely rejected. Recipients of naive kidneys co-transplanted with donor primed cells and kidney grafts from long-term tolerant animals had extended survival times for the naïve renal grafts: 2 out of 3 animals in this group became long-term tolerant and the remaining had an extended graft survival (28 days). These studies demonstrate the first successful adoptive transfer of tolerance in large animals. The data suggest that the tolerated kidneys and cells have regulatory effects, likely due to regulatory T cells that can induce and maintain tolerance. The potency and efficacy of regulatory T cells has been shown in our study and could potentially be exploited to provide for therapies to induce and maintain tolerance.
Thesis (M.A.)--Boston University