HL Exosomes as paracrine signal mediators in cardiac allograft rejection

HL 外泌体作为心脏同种异体移植排斥反应中的旁分泌信号介质

• 批准号: 9005947
• 负责人: Adrian E. Morelli
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-08 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005947
• 关键词: Abdomen; Acute; Adult; Adverse effects; Allogenic; Allografting; Architecture; B-Lymphocytes; Biological; Biology; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cell Communication; Cell surface; Cells; Childhood; Chronic; Development; Disease Marker; Dual-role transvestism; Experimental Designs; Goals; Graft Rejection; Health; Heart Transplantation; Heart failure; Hematological Disease; Immune system; Immunity; Immunosuppressive Agents; In Situ; In Vitro; Lead; Leukocytes; Lung diseases; Lymphoid; Lymphoid Tissue; Maintenance; Mediator of activation protein; Memory; Memory B-Lymphocyte; Messenger RNA; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Organ; Organ Transplantation; Paracrine Communication; Patients; Pharmaceutical Preparations; Proteins; Regimen; Research; Role; Signal Transduction; Staging; T cell response; T-Lymphocyte; Testing; Time; Tissues; Transplant Recipients; Transplantation; Untranslated RNA; Vascular Diseases; Vesicle; allograft rejection; base; cell type; design; exosome; extracellular vesicles; graft failure; heart allograft; in vivo; interest; mouse model; novel therapeutic intervention; novel therapeutics; paracrine; prevent; response; therapy development

 DESCRIPTION (provided by applicant): HL-142. We submit this application in response to the recent NHLBI topic of special interest (TOSI) HL-142 titled "Exosomes as paracrine signal mediators in cardiovascular, lung and blood disease (R01)". Cardiac transplants are the best option for selected pediatric and adult patients with end-stage heart failure. Despite advances in immunosuppressive regimens, graft failure due to rejection and cardiac allograft vasculopathy remains a threat. Therefore, there is a need of new therapies to prevent/treat acute and chronic rejection of cardiac allografts, minimizing the use of immunosuppressive drugs and its side effects. This requires a deeper understanding of the mechanisms of allograft recognition and rejection. This application proposes to investigate the role of cell-to-cell communication via extracellular vesicles (EVs), in particular exosomes, in the allorecognition mechanisms that lead to cardiac graft rejection. Our preliminary studies indicate that the recipient immune system recognizes donor MHC molecules of cardiac allografts as non-self through cell-to-cell communication between donor and recipient leukocytes via exosome-like vesicles (and likely other EVs). Growing evidence indicates that leukocytes and other cell types transfer exosomes and other EVs carrying functional proteins, mRNAs and non-coding RNAs, which exert biological effects on target cells. Our application proposes to study the interaction between donor-derived EVs and the leukocytes of cardiac graft recipients, and the effects of donor EVs on the recipient immune system. The function of exosomes (and other EVs) in vivo remains an enigma. Our experimental approached has been designed to unveil the role of exosomes (and other EVs) in situ and in vivo. If successful, the results will provide one of the first evidences f the biological role of exosomes in vivo. This application will also challenge current paradigms on the mechanism of recognition of transplanted organs by T- and B-lymphocytes of the recipient. We propose the hypothesis that "after heart transplantation, donor exosomes (and other EVs) function as paracrine mediators for passage and dissemination of donor MHC Ag and APC-stimulating signals to recipient APCs. Therefore, donor exosomes (and other EVs) are involved in elicitation and maintenance of acute and chronic rejection of cardiac transplants." We will test our hypothesis in a mouse model of heterotopic (abdomen) cardiac transplantation, in the following Specific Aims: Aim 1: Study the role of donor exosomes (and other EVs) in T-cell allo-recognition after cardiac transplantation, and Aim 2: Study the role of donor-derived exosomes (and other EVs) in elicitation and maintenance of B-cell immunity against cardiac allografts. Our long-term goal is to achieve a better understanding of the mechanisms of heart allograft rejection with the aim of providing new grounds for development of therapies and disease markers based on the biology of EVs.

 描述（由申请人提供）：HL-142。我们提交此申请是为了响应最近的 NHLBI 特别关注主题 (TOSI) HL-142，标题为“外泌体作为心血管、肺和血液疾病的旁分泌信号介质 (R01)”。心脏移植是某些患有终末期心力衰竭的儿童和成人患者的最佳选择，尽管免疫抑制疗法取得了进展，但由于排斥和同种异体心脏移植导致移植失败。因此，需要新的疗法来预防/治疗心脏同种异体移植物的急性和慢性排斥反应，最大限度地减少免疫抑制药物的使用及其副作用，这需要更深入地了解同种异体移植物识别和排斥的机制。本申请旨在研究通过细胞外囊泡（EV）（特别是外泌体）进行的细胞间通讯在导致心脏移植排斥的同种异体识别机制中的作用。受体免疫系统通过供体和受体白细胞之间通过外泌体样囊泡（以及可能的其他 EV）进行细胞间通讯，将心脏同种异体移植物的供体 MHC 分子识别为非自身分子。其他携带功能蛋白、mRNA 和非编码 RNA 的 EV，对靶细胞产生生物学效应，我们的申请旨在研究供体来源的 EV 与心脏移植受体白细胞之间的相互作用。外泌体（和其他 EV）在体内的功能仍然是一个谜，我们的实验方法旨在揭示外泌体（和其他 EV）在原位和体内的作用。如果成功，该结果将为外泌体在体内的生物学作用提供初步证据之一，该应用还将挑战当前接受者 T 淋巴细胞和 B 淋巴细胞识别移植器官的机制。假设“心脏移植后，供体外泌体（和其他 EV）作为旁分泌介质，将供体 MHC Ag 和 APC 刺激信号传递和传播到受体 APC。因此，供体外泌体（和其他 EV）参与引发和维持心脏移植的急性和慢性排斥反应。”我们将测试 我们在异位（腹部）心脏移植小鼠模型中的假设，具体目标如下：目标 1：研究供体外泌体（和其他 EV）在心脏移植后 T 细胞同种异体识别中的作用，目标 2：研究供体来源的外泌体（和其他 EV）在引发和维持针对心脏同种异体移植物的 B 细胞免疫中的作用我们的长期目标是更好地了解心脏机制。同种异体移植排斥，旨在为基于 EV 生物学的疗法和疾病标记物的开发提供新的基础。