Mechanisms of Kidney-Induced Cardiac Allograft Tolerance

肾脏诱导的同种异体心脏移植耐受的机制

• 批准号: 9534853
• 负责人: Joren C Madsen
• 金额: $ 16.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9534853
• 关键词: Acute; Adult; Allograft Tolerance; Allografting; Automobile Driving; Boston; Cells; Chronic; Clinical; Communities; Data; Dendritic Cells; Development; Elements; Environment; Epithelial Cells; Erythrocytes; Erythropoiesis; Erythropoietin; Family suidae; Generations; Goals; Graft Tolerance; Heart; Heart Transplantation; Histocompatibility; Hormones; Human; Immune Tolerance; Immunosuppression; Immunosuppressive Agents; Joints; Kidney; Kidney Transplantation; Knowledge; Life; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Organ; Organ Survival; Organ Transplantation; Outcome; Pathogenicity; Patients; Pharmaceutical Preparations; Production; Protocols documentation; Registries; Regulatory T-Lymphocyte; Resistance; Role; System; T-Lymphocyte; Testing; Transforming Growth Factor beta; Transplant Recipients; Transplantation; Tubular formation; Vascular Diseases; clinical application; design; epidemiology study; experience; heart allograft; immunopathology; improved; improved outcome; isoimmunity; kidney allograft; mortality; mouse model; nonhuman primate; novel strategies; novel therapeutic intervention; programs; public health relevance

 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.

 描述(由申请人提供)：开发诱导和维持健壮的同种异体心脏移植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方案。我们独一无二地证明了小鼠、猪和NHP的肾移植耐受显著促进了心脏移植耐受。了解这些观察结果背后的机制对移植界具有广泛的意义，远远超出了可能接受肾/心脏联合移植的相对较少的患者数量。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(以及其他耐受器官)的耐受，或者在不诱导耐受的情况下改善结果。阐明肾脏诱导的心脏移植耐受(KICAT)的机制是本项目的重点。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)是Kicat的末端效应器，肾脏特异性细胞(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(如促红细胞生成素(EPO))放大了这些调节机制。事实上，新的数据表明，促红细胞生成素(EPO)是一种由成人肾脏产生的激素，以前被认为只会诱导红细胞发育，它通过发挥Treg增强免疫抑制剂的作用来调节肾脏耐受。综上所述，我们的联合数据支持这样的假设：供者移植肾局部高浓度的EPO直接抑制致病效应T细胞，并诱导RTEC和肾脏PDC产生转化生长因子β，从而促进供者反应性Treg的产生和稳定。这些Treg在心脏移植耐受中起着至关重要的作用。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(两个在波士顿的MGH，一个在纽约州的西奈山)，使用小鼠和NHP模型。P.Heeger(纽约州西奈山项目3)将在小鼠身上测试EPO诱导的肾移植耐受的机制。该项目将1)确定肾移植来源的EPO对小鼠同种异体免疫和移植物存活的影响，2)破译EPO抑制传统同种异体反应性T细胞的机制，以及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)将使用小鼠肾脏和心脏/肾脏移植模型来1)确定肾脏诱导系统耐受的一般免疫生物学特征，2)测试Kicat是由调节性耐受还是缺失耐受引起的，以及3)测试特定肾脏来源的细胞和介质负责耐受诱导的假设。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)测试Kicat需要肾脏PDCs和EPO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。该计划是集成的，因此来自小鼠模型的早期进展将为NHP的研究提供信息并加以完善，而NHP的临床发现将在小鼠中进行机械评估。