Mixed chimerism induced tolerance in heart recipients requires donor kidney cotransplantation

项目摘要/摘要与原U01AI131470申请保持不变： 异体肾移植的耐受性在非人类灵长类动物(NHP)和人类中已经实现。 非清髓性预适应和供体骨髓移植(DMBT)的联合应用 在短暂的供体嵌合体中。然而，类似的条件作用未能在心脏受者中诱导耐受性。 尽管存在类似程度的嵌合体。这种器官差异的原因尚不清楚。 然而，很明显，所有移植的器官并不是一模一样的。不仅是强者的力量 对特定器官的免疫反应因移植的器官而异，但反应本身的性质不同， 排斥与耐受，因器官不同而不同。众所周知，某些器官，如肾脏， 和肝脏是耐受的，而其他的，如心脏和肺，是耐受的。在早些时候 使用小型猪进行的研究，我们利用了同种异体肾移植的耐受性，并通过 供体肾与同种异体心脏联合移植，实现移植心脏长期稳定耐受 如果单独移植，就会遭到强烈的排斥。我们现在已经将这些发现扩展到国家卫生保健计划 通过将供体肾联合移植与诱导瞬时供者的混合嵌合体方案相结合 嵌合体。该方案是第一个实现对MHC不匹配的同种异体心脏移植的长期耐受性 国家卫生保健计划。重要的是，每个成功完成方案的受者都实现了无限期的同种异体移植 存活下来，而且没有心脏移植物血管病(CAV)的证据。肾性心脏 同种异体移植的耐受性(Kicat)因其在不同物种中的一致性而变得更加引人注目 (小鼠、猪、NHP)，2)不同的组织相容性屏障，3)不同的耐受方案。这些 研究结果表明，存在能够诱导对任何器官产生耐受性的免疫机制。 阐明这些机制将导致将耐受性扩大到所有同种异体移植接受者的策略。至 为了实现这一目标，我们建议1)研究可能解释耐受性的新机制 肾移植，2)评估独特的调节机制，可促进Kicat，以及3)测试 在实现同种异体心脏移植中不需要供体肾联合移植的替代策略 宽容。我们的具体目标是1)确定MHC是否通过供体微囊(外体)进行交叉修饰 或富含Treg的有组织淋巴结构(TOL)是宿主中观察到的根本区别 移植肾的同种异体反应，2)评价TR1细胞和CD8+CD20+B细胞的作用 细胞到肾脏诱导的同种异体心脏移植耐受，以及3)确定联合小剂量IL-2/抗IL-6R 治疗或供体胸腺联合移植将成功地替代供体肾移植和 实现同种异体心脏移植受者的耐受性。 相关性(请参阅说明)： 这个

The Project Summary / Abstract is unchanged from original U01AI131470 application: Tolerance of kidney allografts has been achieved in non-human primates (NHPs) and in humans using a combination of nonmyeloablative conditioning and donor bone marrow transplantation (DMBT) that results in transient donor chimerism. However, similar conditioning failed to induce tolerance in heart recipients despite comparable levels of chimerism. The reasons for this organ-specific difference are not clear. However, it is clear that all transplanted organs are not created equally. Not only does the strength of the immune response to a particular organ vary with the organ transplanted but the nature of response itself, rejection versus tolerance, varies from organ to organ. It is well known that some organs, such as kidney and liver, are tolerance-prone while others, such as heart and lung, are tolerance-resistant. In earlier studies using miniature swine, we took advantage of the tolerogenicity of kidney allografts and by cotransplanting donor kidneys with heart allografts, achieved long-term stable tolerance of heart allografts which, if transplanted alone, would have rejected acutely. We have now extended those findings to NHPs by combining donor kidney cotransplantation with a mixed chimerism protocol that induces transient donor chimerism. This protocol is the first to achieve long-term tolerance of MHC mismatched heart allografts in NHPs. Importantly, every recipient that successfully completed its protocol achieved indefinite allograft survival and did so without evidence of cardiac allograft vasculopathy (CAV). Kidney-induced cardiac allograft tolerance (KICAT) is made even more compelling by its consistency across 1) different species (mouse, swine, NHP), 2) different histocompatibility barriers, and 3) different tolerance protocols. These findings suggest that immune mechanisms exist which are capable of inducing tolerance to any organ. Elucidating those mechanisms would lead to strategies that extend tolerance to all allograft recipients. To achieve that goal we propose to 1) investigate novel mechanisms that may explain the tolerogenicity of kidney allografts, 2) evaluate unique regulatory mechanisms the may facilitate KICAT, and 3) test alternative strategies that obviate the need for donor kidney cotransplantation in achieving heart allograft tolerance. Our specific aims are 1) to determine if MHC crossdressing via donor microvesicles (exosomes) or Treg-rich organized lymphoid structures (TOLs) underlie the fundamental differences observed in host alloresponses to kidney allografts, 2) to evaluate the contribution of Tr1 cells and a novel CD8+CD20+ B cell to kidney-induced cardiac allograft tolerance, and 3) to determine if combined low dose IL-2/anti-IL-6R therapy or donor thymus cotransplantation will successfully substitute for donor kidney transplantation and achieve tolerance in recipients of isolated heart allografts. RELEVANCE (See instructions): The