The long term goal of this work is to develop a clinical strategy for modulating donor- recipient interactions to promote allograft tolerance, while preserving host responses to infectious challenges. CD40L is a T-cell molecule central to several important pathways driving allograft rejection. Blockade of CD40L (CD154) has shown considerable promise as a foundation upon which to build a tolerogenic strategy. In this application, studies are proposed to 1) establish whether CD40L blockade, alone or in combination with other agents, induces tolerance in nonhuman primates, and 2) to assess the impact of anti-CD40L-based therapy on responses to human influenza virus, an important infectious agent. Based on current understanding of CD40L's role in allograft rejection, more intense perioperative therapy or a higher cumulative dose of anti- CD40L antibody may result in long-term prevalent graft acceptance. An alternate strategy is to add CD40L blockade to a conventional immunosuppressive regimen. A third approach, adding blockade of the costimulatory CD28/B7 pathway to CD40L inhibition, is associated with prevalent rejection-free graft survival in several models. These three candidate strategies will be tested in a primate cardiac allograft model. By examining correlations between graft outcomes and in vitro indices of specific anti-donor immune responses, this proposal addresses important questions regarding how CD40L-dependent interactions modulate allograft rejection. The experiments outlined will also directly assess whether host defenses to influenza virus, an important infectious agent, are regulated by CD40L. Finally, this study will investigate the potential of CD40L inhibition to induce prolonged acceptance of a transplanted organ, and may contribute to development of clinically relevant approaches to the induction of tolerance.
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