Mixed chimerism induced tolerance in heart recipients requires donor kidney cotransplantation

项目摘要/摘要 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。 非清髓性调节和供体骨髓移植(DMBT)的组合导致 一过性供体嵌合体。然而，类似的条件作用未能诱导心脏受者的耐受性，尽管 类似水平的嵌合体。这种器官差异的原因尚不清楚。然而，它是 显然，所有移植的器官并不是一视同仁的。不仅免疫反应的强度 对特定器官的反应因移植器官的不同而不同，但反应本身的性质、排斥反应与 耐受性，因器官而异。众所周知，有些器官，如肾脏和肝脏， 容易耐受，而其他，如心脏和肺，是耐受的。在早期的研究中，使用微型 猪，我们利用了同种异体肾移植的耐受性，并通过将供体肾脏与 同种异体心脏移植，实现了同种异体心脏移植的长期稳定耐受性，如果单独移植， 被尖锐地拒绝。我们现在已经通过联合供体肾联合移植将这些发现扩展到NHP。 用混合嵌合体方案诱导瞬时供体嵌合体。该协议是第一个实现 NHP中MHC不匹配同种异体心脏移植的长期耐受性。重要的是，每个成功的收件人 完成了它的方案，实现了无限期的同种异体移植物存活，而且没有心脏移植物的证据 血管病(CAV)。肾诱导的同种异体心脏移植耐受(Kicat)因其 1)不同物种(小鼠、猪、NHP)的一致性，2)不同的组织相容性障碍，3) 不同的耐受性协议。这些发现表明，免疫机制的存在能够 诱导对任何器官的耐受性。阐明这些机制将导致扩大耐受性的策略 给所有的同种异体移植受者。为了实现这一目标，我们建议1)研究可能解释 肾移植的耐受性，2)评估可能促进Kicat的独特调节机制，以及 3)测试替代策略，以避免在实现心脏移植时需要供体肾脏共同移植 同种异体移植耐受。我们的具体目标是1)确定MHC是否通过供体微泡进行交叉敷料 (外体)或富含Treg的有组织淋巴结构(TOL)是观察到的根本区别 在宿主对同种异体肾移植的反应中，2)评估TR1细胞和新的CD8 CD20的贡献 B细胞对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。

PROJECT SUMMARY / ABSTRACT 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.