The induction of transplantation tolerance has potential to overcome the constraints of lifelong immunosuppressive therapy, which, although currently necessary, is not a satisfactory long-term solution. The overall goal of this program project is to facilitate the translation of allograft tolerance to human transplantation. We will accomplish this by examining novel induction strategies and mechanisms of allograft tolerance in a preclinical rhesus macaque model that is penultimate for human cadaveric donor transplantation, one in which we have a continuing research basis spanning more than two decades. Project 1 will examine a novel strategy for day of transplant tolerance induction that exploits an unusual synergy between the T cell depleting agents, F(Ab)2 of sFv anti-CD3epsilon Immunotoxin (IT), and a potent NF-kappa inhibitor, 15-Deoxyspergualin (DSG), in the early transplant period to induce stable, robust kidney transplant tolerance. The studies focus on immune mechanisms and examine a hypothesis that early arrest and slow recovery of dendritic cell (DC) maturation is a pivotal factor in the induction of tolerance after T cell depletion, while the donor graft provides a critical source of antigen for the maintenance of tolerance. Project 2 will evaluate the ability of their peritransplant Cyclosporin A or DSG, in combination with IT, to promote stable tolerance to islet allografts. These experiments will also examine the ability of gene modification of islets with anti-apoptotic gene Bcl-2, to safeguard islet engraftment during the early injury-prone period, thus maximizing long term graft function. Project 3 will develop customized gene transfer methods by retargeting the tropism of adenovirus for DC via the CD40 pathway. These cells will over-express active TGF-beta1 in a mature donor DC. The Ad TGF-beta1 transduced cells will then be examined as engineered veto cells. As such, the TGF-beta1 transduced DC will deliver a lethal cell cycle arrest signal in the context of T cell-DC co-stimulatory cross talk to the responding donor-reactive T cells. project 4 will examine, in young and old macaques, the thymic dependent and independent pathways for restoration of the T cell receptor repertoire following T cell depletion by immunotoxin and its modulation during allograft tolerance and rejection. This information will have additional utility in other instances of iatrogenic of naturally occurring T cell depletion, as in AIDS models.
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