B cell reaponses and cardiac transplantation in infancy

该项目的总体目标是确定接受婴儿期心脏移植的受者在接受胸腺切除术、短暂T细胞耗竭和免疫抑制治疗后是否会出现B细胞室缺陷。在这些儿童中，由于缺乏新的T细胞产生和短暂的T细胞耗竭，T细胞区室的补偿可能会导致T细胞库严重收缩和T细胞功能改变。由于蛋白抗原抗体的产生和B细胞记忆反应需要T细胞的帮助，这些变化可以改变B细胞区室参与宿主防御和调节自身免疫的能力。本项目中提出的研究将探讨胸腺切除术（在心脏手术的非移植受试者中）和T细胞耗竭和免疫抑制（在婴儿期心脏移植受者中）引起的T细胞区室功能特性的改变是否会损害T细胞依赖性和T细胞非依赖性抗体应答、B细胞记忆的产生和/或维持、B细胞受体多样性和自身抗体产生。这些研究将首次系统分析心脏移植受者的B细胞反应， 移植在婴儿期，并将产生新的基本知识和见解，如何宿主防御可以提高，部分通过设计更有效的免疫。该项目将通过与项目1的合作，研究心脏移植和非移植心脏手术的早期患者。为了研究胸腺切除术、T细胞耗竭、免疫抑制和心脏同种异体移植可能抑制B细胞应答的机制，并测试改善B细胞记忆应答的策略，该项目将研究小鼠（C57 BL/6）。B细胞应答的评价将涉及与项目3合作确定T细胞“帮助”能力，以及与项目4合作分析食蟹猴中的B细胞应答。

The overall goal of this project is to determine whether recipients of cardiac transplants in infancy treated with thymectomy, transient T cell depletion and immunosuppression develop defects in the B cell compartment. In these children, compensation of the T cell compartment for the lack of new T cell production and transient T cell depletion may cause a severely contracted T cell repertoire and altered T cell function. Since production of antibodies to protein antigens and B cell memory responses require T cell help, these changes could modify the ability of the B cell compartment to attend to host defense and to regulate auto-immunity. The research proposed in this project will explore whether altered functional properties of the T cell compartment brought about by thymectomy (in non transplanted subjects of cardiac surgery) and T cell depletion and immunosuppression (in recipients of cardiac transplants in infancy) impair T cell-dependent and T cell independent antibody responses, the generation and/or maintenance of B cell memory, B cell receptor diversity and autoantibody production. These studies will be the first to systematically analyze B cell responses in recipients of cardiac transplants in infancy and will produce new fundamental knowledge and insights into how host defense can be improved, in part through the design of more efficient immunization. The project will study patients with cardiac transplants and non-transplant cardiac surgery early in life through collaboration with Project 1. To investigate the mechanisms by which thymectomy, T cell depletion, immunossupression and cardiac allotransplantation may depress B cell responses and to test strategies to improve B cell memory responses, the project will study mice (C57BL/6). The evaluation of the B cell responses will involve collaborations with Project 3 for determining T cell "help" competency, and with Project 4 to analyze B cell responses in cynomolgus monkeys.