Mechanisms of Kidney-Induced Cardiac Allograft Tolerance

 描述（由申请人提供）：开发诱导和维持强健同种异体心脏移植物的方法是解决与慢性免疫抑制相关的发病率和死亡率的理想解决方案。我们独特地证明了小鼠、猪和 NHP 的肾移植耐受性显着促进了心脏移植耐受性。了解这些观察结果背后的机制对移植界具有广泛的影响，远远超出了可能接受肾脏/心脏联合移植的相对少数患者的范围​​。破译的机制可以指导新的治疗方法，在没有肾脏的情况下诱导对心脏移植物（以及其他耐受性抵抗器官）的耐受性，或在不诱导耐受性的情况下改善结果。阐明肾诱导心脏同种异体移植耐受（KICAT）的机制是该计划的重点。我们在小鼠、猪和 NHP 模型中的初步结果表明，调节性 T 细胞 (Treg) 作为 KICAT 的末端效应器，其中肾脏特异性细胞（例如浆细胞样树突状细胞 (pDC)、肾小管上皮细胞 (RTEC)）和/或细胞产物（即促红细胞生成素 (EPO)）放大了这些调节机制。事实上，新数据表明，促红细胞生成素 (EPO) 是一种由成人肾脏产生的激素，以前被认为仅能诱导红细胞发育，但它通过充当 Treg 增强免疫抑制剂来介导肾脏耐受性。我们的联合数据共同支持以下假设：供体肾移植物中局部高浓度的 EPO 直接抑制致病性效应 T 细胞，并诱导 RTEC 和肾脏 pDC 产生 TGFβ，从而促进供体反应性 Tregs 的生成和稳定性。这些 Treg 细胞在介导心脏移植物耐受性方面发挥着至关重要的作用。为了检验这一假设，我们设计了一个由 3 个使用小鼠和 NHP 模型的交互式项目（2 个在波士顿 MGH 和一个在纽约州西奈山）组成的项目。 P. Heeger（纽约州西奈山，项目 3）将测试 EPO 诱导小鼠肾移植耐受的机制。该项目将 1) 确定同种异体肾移植物衍生的 EPO 对小鼠同种免疫和同种异体移植物存活的影响，2) 破译 EPO 抑制传统同种异体反应性 T 细胞的机制，3) 测试 EPO 对 Treg 诱导和稳定性的机制。 R. Colvin 及其同事（MGH，项目 2）将使用肾脏和心/肾移植的小鼠模型来 1) 确定肾脏诱导的全身耐受性的一般免疫生物学特征，2) 测试 KICAT 是否是由于调节或缺失耐受性，以及 3) 测试特定肾源性细胞和介质负责诱导耐受性的假设。 J. Madsen 及其同事（MGH，项目 1）将 1) 表征 KICAT 诱导的耐受状态的整体稳健性，2) 确定调节性 T 细胞在 KICAT 中的作用，以及 3) 检验肾脏 pDC 和 EPO 是 KICAT 所必需的假设。免疫病理学核心（核心 A）和行政核心将支持所有 3 个项目。该计划是整合的，以便小鼠模型的早期进展将为 NHP 的研究提供信息和完善，同时 NHP 的临床发现将在小鼠中进行机械评估。

 DESCRIPTION (provided by applicant): Developing approaches to induce and maintain robust cardiac allograft is the ideal solution to the morbidity and mortality associated with chronic immunosuppression. We uniquely demonstrated that kidney transplant tolerance in mice, swine and NHP remarkably facilitates heart transplant tolerance. Understanding the mechanisms underlying these observations has broad implications for the transplant community well beyond the relatively small numbers of patients likely to receive kidney/heart cotransplants. The deciphered mechanisms could guide novel therapeutic approaches to induce tolerance to heart grafts (among other tolerance-resistant organs) in the absence of a kidney, or improve outcomes without inducing tolerance. Elucidating mechanisms of kidney induced cardiac allograft tolerance (KICAT) is the focus of this Program. Our preliminary results in murine, swine, and NHP models implicate regulatory T cells (Treg) as the end effectors of KICAT with kidney-specific cells (e.g. plasmacytoid dendritic cells (pDC), renal tubular epithelial cells (RTEC)) and/or cell products (i.e. erythropoietin (EPO)) amplifying those regulatory mechanisms. Indeed, new data indicate that erythropoietin (EPO), a hormone produced by the adult kidney and formerly thought only to induce red blood cell development, mediates kidney tolerance by functioning as a Treg-enhancing immunosuppressant. Together our joint data support the hypothesis that: high local concentrations of EPO in the donor kidney graft directly inhibit pathogenic effector T cells and induce TGFβ production by RTEC and kidney pDC that facilitate generation and stability of donor-reactive Tregs. These Treg crucially mediate heart graft tolerance. To test this hypothesis we have designed a Program consisting of 3 interactive Projects (2 at MGH, Boston and one at Mount Sinai, NY) that use murine and NHP models. P. Heeger (Mount Sinai, NY, Project 3) will test mechanisms of EPO-induced kidney transplant tolerance in mice. The Project will 1) determine the effects of kidney allograft-derived EPO on murine alloimmunity and allograft survival, 2) decipher the mechanisms through which EPO inhibits conventional alloreactive T cells, and 3) test the mechanisms of EPO on Treg induction and stability. R. Colvin and colleagues (MGH, Project 2) will use murine models of kidney and heart/kidney transplantation to 1) determine the general immunobiologic features of kidney induced systemic tolerance, 2) test whether KICAT is due to regulatory or deletional tolerance, and 3) test the hypothesis that specific kidney derived cells and mediators are responsible for tolerance induction. J. Madsen and colleagues (MGH, Project 1) will 1) characterize the overall robustness of the tolerant state induced by KICAT, 2) determine the role of regulatory T cells in KICAT, and 3) test the hypothesis that renal pDCs and EPO are required for KICAT. An immunopathology core (Core A) and the administrative core will support all 3 Projects. This Program is integrated such that early advances from mouse models will inform and refine the studies in NHP while clinical discoveries in NHP will be assessed mechanistically in the mouse.