Cellular Strategies for Tolerance Induction

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Renal transplantation represents first-line therapy for patients with ESRD, with the most recent data documenting significant one-year success rates. However, patients continue to face high morbidity and mortality after transplant, both from chronic allograft rejection and from the toxicities associated with standard immunosuppressive regimens. Given these dual risks, the ultimate goal in this field is the induction of immune tolerance after transplantation, which promises life-long acceptance of an allograft, without the need for ongoing immunosuppression and importantly, with preservation of protective immunity. While novel pharmacologic and antibody-based therapies represent real promise in terms of greatly prolonging allograft survival and reducing off-target toxicities, murine studies strongly suggest that the most robust strategies for inducing immune tolerance incorporate cellular therapies, including both mixedchimerism induction (especially in combination with T cell costimulation blockade) and regulatory T cell (Treg)-based approaches. Both of these therapies hold the promise of fundamentally resetting recipient immunity in favor of allograft acceptance, and thus provide a direct pathway towards immune toleranceinduction. In this Project, we will explore the following Aims, each designed to advance the use of cellular therapies for tolerance induction after renal transplantation: Specific Aim #1: To induce immune tolerance to a renal allograft through the induction of stable, full-spectrum mixed-hematopoietic chimerism in the setting of T cell costimulation blockade. Specific Aim #2: To utilize regulatory T cells to induce stable, full-spectrum mixed-chimerism and immune tolerance during renal transplantation.