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: 9217670
• 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/9217670
• 关键词: Abdomen; Acute; Adult; Adverse effects; Allogenic; Allografting; Architecture; Awareness; B-Lymphocytes; Biological; Biology; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cell Communication; Cell surface; Cells; Childhood; Chronic; Development; Disease Marker; Experimental Designs; Goals; Graft Rejection; 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; 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; public health relevance; 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.