Optimizing Mixed chimerism for Heart Transplantation in Nonhuman Primates

在非人灵长类动物（NHP）中已经实现了对同种异体肾移植的耐受性， 使用非清髓性预处理和供体骨髓移植的组合的人， 导致短暂的供体嵌合。然而，诱导长期耐受的混合嵌合体方案， NHP中的肾同种异体移植物在心脏同种异体移植物的受体中不能这样做。项目1的目标是使用新的 优化混合嵌合体的药物和新策略，以诱导心脏同种异体移植物耐受 预防心脏移植物血管病变（CAV）。我们假设1）针对新认识的 耐受的障碍将使我们能够改变同种反应的平衡，远离同种攻击， 导致长期耐受的缺失/调节，2）体液反应和促炎状态 对心脏移植物接受者的耐受诱导特别有害， 限制混合嵌合状态持续时间的混杂因素，和3）持久的混合嵌合状态 心脏移植受者的耐受性可能需要，因为与肾脏不同，心脏移植物不 一旦嵌合体消失，似乎能够维持耐受性。在每个项目的具体目标中， 同种异体、自体和天然抗体对混合嵌合体诱导后移植物丢失的贡献是 以创新和互补的方式得到承认和处理。同样， 促炎分子被认为是整个计划，并解决了创新和 互补的方法。我们预计目前的进展将继续有助于减少 与实体器官移植相关的发病率和死亡率。 相关性（参见说明）： 人类心脏移植受者的存活受到排斥反应和抗-HCV并发症的限制。 排异药物该建议的目的是在接受者中诱导免疫耐受状态， 它“欺骗”免疫系统，使其将外来移植物视为自己的组织， 不需要药物就能被拒绝这将大大改善心脏移植的效果。

Tolerance to kidney allografts has been achieved in nonhuman primates (NHPs) and, for the first time, in humans using a combination of nonmyeloablative conditioning and donor bone marrow transplantation that results in transient donor chimerism. However, mixed chimerism protocols that induce long term tolerance to kidney allografts in NHPs fail to do so in recipients of cardiac allografts. The goal of Project 1 is to use new agents and novel strategies to optimize mixed chimerism so that it will induce tolerance to cardiac allografts and prevent cardiac allograft vasculopathy (CAV). We hypothesize that 1) targeting newly recognized barriers to tolerance will allow us to alter the balance of an alloresponse away from alloaggression and towards deletion/regulation leading to long-term tolerance, 2) humoral responses and proinflammatory states are particularly detrimental to tolerance induction in cardiac allograft recipients and may be important confounding factors limiting the duration of the state of mixed chimerism, and 3) durable mixed chimerism will likely be required for tolerance in heart recipients because, unlike kidneys, cardiac allografts do not appear capable of maintaining tolerance once chimerism disappears. In the specific aims of each Project, the contributions of allo-, auto- and natural antibodies to graft loss after mixed chimerism induction are recognized and addressed in an innovative and complementary manner. Likewise, the deleterious effects of proinflammatory molecules are considered throughout the program and addressed with innovative and complementary approaches. We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. RELEVANCE (Seeinstructions): The survival of human recipients of heart transplants is limited by rejection and by the complications of anti- rejection drugs. The objective of this proposal is to induce a state of immune tolerance in the recipient, which "tricks" the immune system into seeing the foreign graft as its own tissue, so that the organ is not rejected without the need for drugs. This would greatly improve the outcomes of heart transplants.