B cell reaponses and cardiac transplantation in infancy

婴儿期 B 细胞反应和心脏移植

• 批准号: 7312641
• 负责人: MARILIA Isabel CASCALHO
• 金额: $ 32.26万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312641
• 关键词: B lymphocyte; antigen antibody reaction; artificial immunosuppression; autoimmunity; clinical research; heart transplantation; human subject; human therapy evaluation; humoral immunity; immunologic memory; immunoregulation; infant human (0-1 year); laboratory mouse; leukocyte depletion therapy; microarray technology; patient oriented research; postoperative complications; therapy adverse effect; thymectomy; transplantation immunology

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.

该项目的总体目标是确定接受胸腺切除、一过性T细胞耗竭和免疫抑制治疗的婴儿心脏移植的受者是否会出现B细胞室缺陷。在这些儿童中，T细胞室对缺乏新的T细胞产生和一过性T细胞耗竭的补偿可能会导致T细胞库严重收缩和T细胞功能改变。由于产生针对蛋白质抗原的抗体和B细胞记忆反应需要T细胞的帮助，这些变化可能会改变B细胞隔间负责宿主防御和调节自身免疫的能力。这项研究将探索胸腺切除(在心脏手术的非移植受试者中)和T细胞耗竭和免疫抑制(在婴儿接受心脏移植的受者中)带来的T细胞室功能特性的改变是否会损害T细胞依赖和T细胞非依赖的抗体反应、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的产生。这些研究将首次系统地分析心脏移植受者的B细胞反应。 在婴儿期进行移植，将产生新的基础知识，并将部分通过设计更有效的免疫来改善宿主防御。该项目将通过与项目1的合作，研究生命早期接受心脏移植和非移植心脏手术的患者。为了研究胸腺切除、T细胞耗尽、免疫抑制和心脏同种异体移植可能抑制B细胞反应的机制，并测试改善B细胞记忆反应的策略，该项目将以小鼠为研究对象(C57BL/6)。B细胞反应的评估将涉及与项目3合作确定T细胞“帮助”能力，并与项目4合作分析食蟹猴的B细胞反应。