Mechanisms of Kidney-Induced Cardiac Allograft Tolerance

 描述（由申请人提供）：开发诱导和维持稳健心脏同种异体移植物的方法是解决慢性免疫抑制相关发病率和死亡率的理想方案。我们独特地证明了小鼠、猪和NHP的肾移植耐受性显著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有着广泛的影响，远远超出了可能接受肾/心脏联合移植的相对少数患者。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（以及其他耐受性器官）的耐受，或者在不诱导耐受的情况下改善结果。肾诱导心脏移植耐受（KICAT）的机制是本项目的重点。我们在鼠、猪和NHP模型中的初步结果表明，调节性T细胞（Treg）作为KICAT的末端效应物，肾特异性细胞（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））放大这些调节机制。事实上，新的数据表明，促红细胞生成素（EPO），一种由成人肾脏产生的激素，以前认为只会诱导红细胞发育，通过作为Treg增强免疫抑制剂介导肾脏耐受。总之，我们的联合数据支持以下假设：供体肾移植物中高局部浓度的EPO直接抑制致病性效应T细胞，并诱导RTEC和肾pDC产生TGFβ，从而促进供体反应性T细胞的产生和稳定性。这些Treg关键地介导心脏移植耐受。为了验证这一假设，我们设计了一个由3个互动项目组成的项目（2个在MGH，Boston，1个在Mount Sinai，NY），使用小鼠和NHP模型。P. Heeger（Mount Sinai，NY，项目3）将在小鼠中测试EPO诱导的肾移植耐受性的机制。该项目将1）确定肾同种异体移植物衍生的EPO对小鼠同种异体免疫和同种异体移植物存活的影响，2）破译EPO抑制常规同种异体反应性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）将使用肾脏和心脏/肾脏移植的小鼠模型来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是否是由于调节性或缺失性耐受性，以及3）测试特定肾脏来源的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诱导的耐受状态的总体稳健性，2）确定调节性T细胞在KICAT中的作用，3）检验肾pDC和EPO是KICAT所需的假设。免疫病理学核心（核心A）和行政核心将支持所有3个项目。该计划的整合使得小鼠模型的早期进展将为NHP的研究提供信息和完善，而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.