Cardiac Transplantation in Infancy

描述（由申请人提供）：本项目探讨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，但它可能对免疫系统产生深远的、迄今为止尚未认识到的影响。患者需要切除胸腺和消耗T细胞，因此可能出现T细胞和依赖T细胞的B细胞反应缺陷。因为移植是在生命早期进行的，接受者可能会对它携带的抗原产生自发的耐受性。而且，由于记忆淋巴细胞很少，年幼的婴儿可能非常适合通过刻意的努力来诱导耐受性。本节目将探讨心脏移植对年轻人的影响。在项目1“婴儿心脏移植的免疫学”中，将讨论对血型或主要组织相容性抗原的耐受性是否在移植后自发产生，以及移植物是否被调节。在项目2“婴儿时期的B细胞反应和心脏移植”中，将讨论在婴儿时期接受心脏移植的患者是否可以产生正常的T细胞独立和T细胞依赖的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，胸腺切除术和T细胞消耗是否会引起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将得到解决。在项目4“新生儿猴心脏异体移植耐受”中，将研究非人类灵长类动物，以确定对血型或MHC抗原的耐受是否自发产生，以及对受体的操作（如胸腺移植）是否可以提高免疫能力。该计划将由一个行政核心（核心A）提供支持，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，以及与母研究所的互动。该项目将由实验室核心（Core B）提供支持，该实验室将分析淋巴细胞受体多样性、病毒载量、自身抗体水平，并审查各种项目共有的病理标本。项目1：婴儿心脏移植免疫学，多伦多儿童医院，加拿大；项目2：婴儿B细胞反应和心脏移植，明尼苏达州罗彻斯特；项目3：婴儿T细胞反应和心脏移植，明尼苏达州罗彻斯特；新生猴子心脏异体移植耐受性研究，西安大略大学伦敦分校，安大略省，加拿大

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