Cardiac Transplantation in Infancy

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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