Optimizing Mixed chimerism for Heart Transplantation in Nonhuman Primates

在非人类灵长类动物(NHP)中已经实现了对同种肾脏移植的耐受性，并首次在 使用非清髓性调节和供体骨髓移植相结合的人类 导致一过性供体嵌合体。然而，诱导长期耐受的混合嵌合体方案 NHP中的同种异体肾移植在心脏移植受者中未能做到这一点。项目1的目标是使用新的 优化混合嵌合体以诱导同种异体心脏移植耐受的药物和新策略 并预防心脏移植物血管病(CAV)。我们假设1)目标是新认识到的 容忍的障碍将使我们能够改变同种反应的平衡，而不是同种侵略和 导致长期耐受的缺失/调节，2)体液反应和促炎状态 尤其不利于诱导同种异体心脏移植受者的耐受，并且可能是重要的 限制混合嵌合体状态持续时间的混杂因素，以及3)持久的混合嵌合体 很可能是心脏受者的耐受性所必需的，因为与肾脏不同，心脏移植不需要 一旦嵌合体消失，看起来有能力维持容忍。在每个项目的具体目标中， 混合嵌合体诱导后，异体抗体、自身抗体和天然抗体对移植物丢失的作用如下 以创新和相辅相成的方式认识和解决这些问题。同样，它的有害影响 促炎分子在整个计划中都得到了考虑，并通过创新和 互补的方法。我们预计，正在进行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(请参阅说明)： 人类心脏移植受者的存活受到排斥和抗排斥并发症的限制。 排斥性药物。这一建议的目的是在接受者中诱导一种免疫耐受状态， 这“诱骗”免疫系统将异体移植物视为自己的组织，这样器官就不会 不需要药物就被拒绝了。这将极大地改善心脏移植的结果。

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.