Our central hypothesis is that induction of robust, reproducible and durable tolerance to cardiac allografts will 1) result in long-term graft survival, 2) preserve normal graft function, and 3) prevent cardiac allograft vasculopathy (CAV). However, we cannot base the development of clinical tolerance strategies aimed at heart transplant recipients on studies in other organs and we should not assume that every protocol that promotes long-term survival will protect the graft from development of progressive CAV. Instead, the most effective tolerance strategies from rodent studies must be specifically tested in large animal models of heart transplantation. The cynomolgus monkey heart transplant model provides an ideal system for both tasks because of the similarity of their immune system to that of humans, the large number of reagents available for mechanistic assays, and the well-characterized development of CAV in these animals. We will test the ability of novel tolerance induction strategies to induce tolerance to cardiac allografts and prevent CAV, and assess biomarkers of the tolerant state. Our aims are to, 1) determine whether a regimen that uses agonist-type IL-2/Fc and mutant antagonist-type IL-15/Fc fusion proteins with sirolimus can induce tolerance to cardiac allografts, 2) determine whether combining the agonist IL-2/antagonist IL-15/sirolimus regimen with vascularized donor thymus transplantation or a mixed chimerism conditioning regimen will improve the longevity of tolerance and prevent CAV and 3) devise a set of biomarkers which will reflect the establishment and/or loss of tolerance.