CD4 Memory T Cells and Allograft Rejection

特异于供体抗原的记忆T细胞在移植中提出了独特的挑战。当记忆T 细胞增强宿主对再感染的保护，供体反应性记忆T细胞导致强大的免疫应答。 对移植器官的反应转化为人类同种异体移植结果不良的风险增加。 此外，记忆性T细胞似乎对目前使用的移植物延长疗法的效果有抵抗力 包括免疫抑制药物、耗竭策略和常规共刺激阻断。的 存在两个群体的记忆CD 4 T细胞已提出基于不同的迁移 特性.虽然中枢记忆性CD 4 T细胞存在于次级淋巴器官中，但效应记忆性CD 4 T细胞存在于次级淋巴器官中。 细胞优先通过非淋巴外周组织循环并进行病原体监视。的 这些记忆性C 04 T细胞亚群的功能，它们对同种异体移植物排斥的贡献和对 目前使用的免疫疗法仍是未知的，需要进行测试。建议的目标 研究的目的是确定淋巴和外周同种异体反应性记忆CD 4 T的解剖学定位， 细胞影响它们的活化、功能和对淋巴隔离和共刺激的敏感性。 封锁我们假设淋巴样而非外周记忆性CD 4 T细胞有助于心脏 通过诱导供者反应性CDST细胞和同种抗体， 外周记忆CD 4 T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，记忆辅助功能需要共刺激ICOS/B7 RP-1相互作用 CD 4 T细胞和记忆和新产生的效应T细胞迁移到移植物中。测试 根据这一假设，我们建议比较淋巴细胞和外周细胞的迁移特性和功能， 记忆CD 4 T细胞，以测试淋巴隔离对淋巴细胞功能的影响， 外周同种异体反应性记忆CD 4 T细胞，并确定通过ICOS/B7 RP共刺激的作用- 1在淋巴和外周记忆CD 4 T细胞的再活化、运输和功能中的作用。 所提出的实验的结果将提供机制的见解，免疫生物学的 同种异体反应性记忆CD 4 T细胞在同种异体移植排斥反应中的作用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.