Mixed chimerism induced tolerance in heart recipients requires donor kidney cotransplantation

混合嵌合体诱导的心脏受体耐受需要供体肾脏联合移植

• 批准号: 9925753
• 负责人: Joren C Madsen
• 金额: $ 85.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925753
• 关键词: Acute; Allogenic; Allograft Tolerance; Allografting; Appearance; B-Lymphocytes; Bone Marrow Transplantation; CD8B1 gene; Cells; Chimerism; Chronic; Clinical Protocols; Communities; Dose; Elements; FOXP3 gene; Family suidae; Goals; Heart; Heart Transplantation; Histocompatibility; Human; Immune; Immune response; Immunosuppression; Interleukin-2; Kidney; Kidney Transplantation; Lead; Life; Liver; Lung; MS4A1 gene; Miniature Swine; Mus; Nature; Organ; Organ Transplantation; Patients; Pharmaceutical Preparations; Population; Protocols documentation; Regulatory T-Lymphocyte; Resistance; Role; T-Lymphocyte; Testing; Thymus Gland; Time; Transplant Recipients; Transplantation; Vascular Diseases; cell type; conditioning; exosome; heart allograft; kidney allograft; lymphoid structures; microvesicles; nonhuman primate; novel; novel therapeutic intervention; response; thymus transplantation

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.

项目总结/摘要 在非人灵长类动物（NHP）和人类中，使用免疫组织化学方法已经实现了肾移植的耐受性。 非清髓性预处理和供体骨髓移植（DMBT）的组合，导致 短暂供者嵌合体然而，类似的预处理未能诱导心脏受体的耐受性， 嵌合体水平相当。这种器官特异性差异的原因尚不清楚。但据 很明显，所有移植的器官都不是平等的。不仅免疫反应的强度 对特定器官的反应随移植的器官而异，但反应本身的性质，排斥与 耐受性因器官而异。众所周知，一些器官，如肾脏和肝脏， 而其他的，如心脏和肺，是耐受性的。在早期的研究中， 猪，我们利用了同种异体肾脏移植的耐受性，并通过与猪共移植供体肾脏， 心脏同种异体移植，实现了长期稳定的心脏移植耐受性，如果单独移植， 断然拒绝。我们现在通过联合供肾共移植将这些发现扩展到NHP 用诱导瞬时供体嵌合的混合嵌合方案。该协议是第一个实现 NHP患者MHC不匹配心脏移植物的长期耐受性重要的是，每一个成功的接受者 完成了其方案，实现了无限期的移植物存活，并且没有心脏移植的证据 血管病变（CAV）。肾诱导的心脏移植耐受（KICAT）由于其 1）不同种属（小鼠、猪、NHP）之间的一致性，2）不同组织相容性屏障，以及3） 不同的容忍协议。这些发现表明，存在免疫机制， 对任何器官都有耐受性。阐明这些机制将导致延长耐受性的策略 所有同种异体移植受者。为了实现这一目标，我们建议1）研究新的机制，可以解释 肾同种异体移植物的致耐受性，2）评价可能促进KICAT的独特调节机制，以及 3)测试替代策略，以减少供体肾共移植的需要， 同种异体移植耐受我们的具体目标是：1）确定MHC是否通过供体微囊泡 （外泌体）或富含Treg的有组织淋巴结构（TOLs）是观察到的根本差异的基础。 2）评估Tr 1细胞和一种新的CD 8 + CD 20 + T细胞的作用， B细胞对肾诱导的心脏同种异体移植物耐受，和3）确定组合的低剂量IL-2/抗IL-6 R 治疗或供者胸腺共移植将成功地替代供者肾移植， 在离体心脏移植的受者中实现耐受。