CD4 Memory T Cells and Allograft Rejection

针对供体抗原的记忆T细胞在移植中是一个独特的挑战。当内存T 细胞在再次感染时增强宿主保护，供者反应性记忆T细胞导致强大的免疫 对移植器官的反应会增加人类同种异体移植结果不良的风险。 此外，记忆T细胞似乎对目前使用的移植物延长疗法的效果具有抵抗力 包括免疫抑制药物、耗竭策略和常规的共刺激阻断。这个 基于不同的迁移，提出了两种记忆CD4T细胞的存在 属性。虽然中央记忆CD4T细胞驻留在次级淋巴器官中，但效应器记忆CD4T 细胞优先在非淋巴组织中循环，并进行病原体监测。这个 这些记忆C04 T细胞亚群的功能，它们在同种异体移植排斥反应和易感性中的作用 目前使用的免疫疗法仍不清楚，需要进行测试。建议的目标是 研究是确定淋巴和外周同种异体反应记忆CD4T的解剖位置 细胞影响其活性、功能和对淋巴隔离和共刺激的敏感性 封锁。我们假设淋巴系而不是外周记忆CD4T细胞对心脏有贡献 通过帮助诱导供者反应性CDST细胞和同种异体抗体实现同种异体移植排斥反应 外周记忆CD4T细胞迁移到移植物中，并表达介导组织损伤的功能。我们 进一步假设记忆的辅助功能需要共刺激的ICOS/B7RP-1相互作用 CD4T细胞以及记忆T细胞和新生成的效应T细胞向移植物的迁移。为了测试 在这一假设下，我们提出比较淋巴系和外周淋巴系的迁移特性和功能 记忆CD4T细胞，检测淋巴滞留对淋巴免疫功能的影响 外周同种异体反应性记忆CD4T细胞，并通过ICOS/B7RP-确定共刺激的作用 1在淋巴和外周记忆CD4T细胞的再激活、运输和功能中起重要作用。 拟议中的实验结果将为人类免疫生物学提供机械性的见解。 同种异体反应性记忆CD4T细胞与同种异体移植排斥反应这些信息应该有助于发展 联合治疗以改善致敏患者的同种异体移植物功能和存活率。

Memory T cells specific for donor antigens present a unique challenge in transplantation. While memory T cells augment host protection upon re-infection, donor-reactive memory T cells lead to robust immune responses to a transplanted organ translating into increased risk of poor allograft outcome in humans. Furthermore, memory T cells appear to be resistant to the effects of currently used graft-prolonging therapies including immunosuppressive drugs, depletional strategies and conventional costimulatory blockade. The existence of two populations of memory CD4 T cells has been proposed based on distinct migratory properties. While central memory CD4 T cells reside in secondary lymphoid organs, effector memory CD4 T cells preferentially circulate through non-lymphoid peripheral tissues and perform pathogen surveillance. The functions of these memory C04 T cells subsets, their contribution to allograft rejection and susceptibility to the currently used immunotherapies remain unknown and need to be tested. The goal of the proposed studies is to determine how the anatomical location of lymphoid and peripheral alloreactive memory CD4T cells affects their activation, function and susceptibility to lymphoid sequestration and to costimulatory blockade. We hypothesize that lymphoid but not peripheral memory CD4T cells contribute to cardiac allograft rejection by providing help for the induction of donor-reactive CDST cells and alloantibody while peripheral memory CD4T cells migrate into the graft and express functions mediating tissue damage. We further hypothesize that costimulatory ICOS/B7RP-1 interactions are required for helper functions ofmemory CD4 T cells and for the migration of both memoryand newly generated effector T cells into the graft. To test this hypothesis, we propose to comparethe migratory properties and functions of lymphoid versus peripheral memory CD4 T cells, to test the effect of lymphoid sequestration on the function of lymphoidversus peripheral alloreactive memory CD4 T cells, and to determine the role of costimulation through ICOS/B7RP- 1 in the re-activation, trafficking and functions of lymphoid and peripheral memory CD4T cells. The results of the proposed experiments will provide mechanistic insights into the immunobiology of alloreactive memory CD4 T cells in allograft rejection. This information should contribute to the development of combinatorial therapies to improve allograft function and survival in sensitized patients.