Cardiac Transplantation in Infancy

描述(由申请者提供)：该计划探索婴儿心脏移植对免疫系统的影响。心脏移植纠正了严重先天性心脏病和心肌病的破坏性生理学，但它可能对免疫系统产生深远的、迄今尚未被认识到的影响。患者的胸腺被切除，T细胞被耗尽，因此可能会出现T细胞和T细胞依赖的B细胞反应缺陷。由于移植是在生命早期进行的，受者可能会对其携带的抗原产生自发的耐受性。而且，由于几乎没有记忆淋巴细胞，幼小的婴儿可能非常适合刻意地努力诱导耐受。本节目将探讨心脏移植在年轻人中的这些和其他影响。在项目1“婴儿心脏移植物的免疫学”中，将解决移植后是否自发产生对血型或主要组织相容性抗原的耐受性以及移植物是否能够适应的问题。在项目2“婴儿期的B细胞反应和心脏移植”中，将讨论在婴儿期接受心脏移植的患者是否可以获得正常的T细胞非依赖性和T细胞依赖性的B细胞反应，包括对疫苗的反应，以及这些反应是否可以通过修改方案或免疫原来改善。在项目3“婴儿期的T细胞反应和心脏移植”中，将解决胸腺切除和T细胞耗尽是否会导致T细胞室结构或功能的变化，以及这些变化是否可以通过各种措施逆转的问题。在项目4中，将对非人类灵长类动物进行研究，以确定对血型或MHC抗原的耐受性是否是自发产生的，以及对受体的操作，如胸腺移植，是否可以提高免疫能力。该方案将得到一个行政核心(核心A)的支持，该核心将组织项目成员与内部和外部咨询委员会之间的数据共享和沟通，以及与上级研究所的互动。该计划将得到实验室核心(核心B)的支持，该实验室将对淋巴细胞受体多样性、病毒载量、自身抗体水平进行分析，并审查各种项目常见的病理标本。计划项目设施，管理核心和实验室核心：明尼苏达州罗切斯特的梅奥诊所，项目1：婴儿心脏移植物的免疫学，加拿大多伦多患病儿童医院，项目2：婴儿时期的B细胞反应和心脏移植，明尼苏达州罗切斯特，项目3：婴儿时期的T细胞反应和心脏移植，明尼苏达州罗切斯特，项目4：走向新生猴子的心脏移植耐受，加拿大安大略省伦敦西安大略大学

DESCRIPTION (provided by applicant): This program explores the implications for the immune system of cardiac transplantation in infancy. Cardiac transplantation corrects the devastating physiology of severe congenital heart disease and cardiomyopathy, but it may have a profound and heretofore unrecognized impact on the immune system. The patient is subjected to removal of the thymus and depletion of T cells, and thus might develop defects in T cell and T cell dependent B cell responses. Because the transplant is performed early in life, the recipient may develop spontaneous tolerance to the antigens it carries. And, having few memory lymphocytes, the young infant may be ideally suited for deliberate efforts to induce tolerance. This program will explore these and other implications of cardiac transplantation in the young. In Project 1 "Immunology of cardiac grafts in infants," the questions of whether tolerance to blood group or major histocompatibility antigens arises spontaneously following transplantation and whether the graft becomes accommodated will be addressed. In Project 2 "B cell responses and cardiac transplantation in infancy," the questions of whether patients who receive cardiac transplants in infancy can mount normal T cell independent and T cell dependent B cell responses, including responses to vaccines, and whether these responses can be improved by modifying the regimen or the immunogen will be addressed. In Project 3 "T cell responses and cardiac transplantation in infancy," the questions of whether thymectomy and T cell depletion cause changes in the structure or function of the T cell compartment, and whether these changes can be reversed by various measures will be addressed. In Project 4 "Toward cardiac allograft tolerance in newborn monkeys" non-human primates will be studied to determine whether tolerance to blood group or MHC antigens arises spontaneously, and whether manipulations of the recipient, such as thymus transplantation, can improve immune competence. The program will be supported by an Administrative Core (Core A), which will organize the sharing of data and communication between members of the projects and the Internal and External Advisory Committees and interactions with the parent Institute. The program will be supported by a Laboratory Core (Core B), which will perform analysis of lymphocyte receptor diversity, viral load, auto-antibody levels and review of pathologic specimens common to the various projects. Program Project Facility, Administrative Core, and Laboratory Core: Mayo Clinic, Rochester, Minnesota Project 1: Immunology of cardiac grafts in infants, The Hospital for Sick Children, Toronto, Canada Project 2: B cell responses and cardiac transplantation in infancy, Rochester, Minnesota Project 3: T cell responses and cardiac transplantation in infancy, Rochester, Minnesota Project 4: Toward cardiac allograft tolerance in newborn monkeys, The University of Western Ontario London, Ontario, Canada