Tolerance to Allogeneic Hearts via Implantation of Cultured Donor Thymus

Duke University, Durham NC

Investigators

Abstract

ABSTRACT: Tolerance to Allogeneic Hearts via Implantation of Cultured Donor Thymus Advances in immunosuppression have improved patient outcomes after allogeneic heart transplantation, but patients remain at risk for life-threatening infection, chronic rejection, and end-organ failure. Development of tolerance to the transplanted heart would reduce or eliminate the need for continuing immuno-suppression, which should improve both allograft and patient survival. Our goal is to use donor thymus tissue to induce central tolerance to a heart transplanted from the same donor. We have shown that cultured allogeneic thymus tissue implantation (CTTI) into athymic children can establish a fully functional immune system that is tolerant to MHC antigens present on the donor thymus as well as on recipient tissues. We showed that CTTI can also induce robust donor-specific tolerance in immunocompetent rat recipients of allogeneic hearts matched to the thymus donor. This project will extend these exciting and potentially paradigm-changing discoveries to an immunocompetent large animal model where clinical safety and efficacy of tolerance induction via CTTI can be assessed in preparation for human clinical trials. The specific aims are: 1) To assess the safety and efficacy of cultured thymus tissue implantation (CTTI) for induction of tolerance to co-transplanted same-donor cardiac allografts in young miniature swine; 2) To determine the efficacy of CTTI using thymus from young adult donors for immune reconstitution and tolerance development in miniature swine; and 3) To develop evidence-based inclusion criteria for expanding the human thymus donor pool across the age range of potential allograft donors. These studies leverage our unparalleled expertise in human thymus biology, clinical CTTI, and heart transplantation to induce central tolerance to transplanted hearts. Results will be applicable to recipients of all types of allografts and should provide additive or synergistic benefits when combined with tolerance-inducing therapies that act on cells in the periphery. Together, these studies will advance toward the long sought-after goal of generating the robust tolerance of transplanted organs that is needed to markedly improve the survival of allografts and recipients.