We hypothesize that stably-immature dendritic cells (DC) can be employed in tolerance-enhancing strategies to promote donor-specific tolerance to renal allografts in the rhesus macaque. In our own and others'recent small animal studies, indefinite organ graft survival enabled by 'DC therapy', is associated with the absence of transplant vasculopathy and the generation of T regulatory cells (Treg) that infiltrate the graft and confer resistance to rejection in naive recipients. In human volunteers, as few as 2.106 immature, autologous DC promote T cell tolerance to model Ags. We have generated 'negative DC vaccines'that resemble tolerogenic DC in humans and rodents by propagating rhesus monocyte-derived DC in vitamin DC and IL-10. Allogeneic recipients infused systemically with these DC in combination with T cell costimulation blockade, develop T cell hyporesponsiveness to donor, with the emergence of CD4+ IL-10+T cells (putative regulatory T cells). Our rodent studies show that combination of similar, stably-immature DC with costimulation blockade or a sub-therapeutic course of rapamycin results in indefinite graft survival. We have 3 specific aims:
AIM I : TO COMPARE THE ABILITY OF MATURATION-RESISTANT, DONOR VERSUS RECIPIENT RHESUS DC TO REGULATE ALLOIMMUNE RESPONSES. We will seek to elucidate both in vitro and in vivo how stably-immature DC regulate alloreactive T cells responses, in particular the role of Treg, and ascertain the comparative efficacy of donor-versus-recipient DC.
AIM II :TO ASCERTAIN THE EFFICACY OF TOLEROGENIC DC IN RHESUS RENAL TRANSPLANTATION AND THEIR IMPACT ON MECHANISMS UNDERLYING IMMUNE REGULATION. Donor and recipient-derived DC will be compared for their ability to prolong renal allograft survival and regulate anti-donor responses in graft recipients.
AIM III : TO DETERMINE THE EXTENT TO WHICH CD40-CD154 PATHWAY BLOCKADE AND RAPAMYCIN AUGMENT THE POTENTIAL OF IMMATURE DC TO PROMOTE LONG-TERM, REJECTION-FREE, RENAL ALLOGRAFT SURVIVAL. We will establish the capacity of anti-GDI 54 mAb and the """"""""tolerance-sparing"""""""" drug rapamycin to enhance DC tolerogenicity and their potential to promote donor-specific tolerance in the renal transplant model. Excellent facilities and extensive expertise in NHP organ transplantation, post-transplant monitoring (including immunologic monitoring) and experience with relevant therapeutic agents in primates are available to enable and sustain these studies. In clinical transplantation, pre-emptive conditioning of the prospective graft recipient by infusion of in vitro-expanded """"""""tolerogenic"""""""" DC (either donor-derived DC or donor allo-Ag-pulsed, recipient DC) is clearly feasible in relation to live donor renal, liver or lung transplantation and may result in donor-specific tolerance.
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