CD4 Memory T Cells and Allograft Rejection

描述（由申请人提供）：对供体抗原特异性的记忆T细胞在移植中提出了独特的挑战。记忆T细胞在再次感染时增强宿主保护，供体反应性记忆T细胞会导致对移植器官的强大免疫反应，从而增加人类同种异体移植预后不良的风险。此外，记忆T细胞似乎对目前使用的移植物延长疗法（包括免疫抑制药物、消耗策略和传统的共刺激阻断）的作用具有抗性。基于不同的迁移特性，两种记忆性CD4 T细胞的存在被提出。中枢记忆性CD4 T细胞存在于次级淋巴器官，而效应记忆性CD4 T细胞优先在非淋巴外周组织循环并执行病原体监测。这些记忆CD4 T细胞亚群的功能，它们对同种异体移植排斥反应的贡献以及对目前使用的免疫疗法的敏感性仍然未知，需要进行测试。拟议研究的目的是确定淋巴细胞和外周同种反应性记忆CD4 T细胞的解剖位置如何影响它们的激活、功能和对淋巴细胞隔离和共刺激阻断的易感性。我们假设淋巴细胞而非外周记忆性CD4 T细胞通过帮助诱导供体反应性CD8 T细胞和同种异体抗体参与心脏移植排斥反应，而外周记忆性CD4 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，共刺激ICOS/B7RP-1相互作用是记忆CD4 T细胞辅助功能以及记忆和新产生的效应T细胞迁移到移植物中所必需的。为了验证这一假设，我们建议比较淋巴样细胞和外周记忆性CD4 T细胞的迁移特性和功能，测试淋巴样细胞隔离对淋巴样细胞和外周同种反应性记忆性CD4 T细胞功能的影响，并确定通过ICOS/B7RP- 1共刺激在淋巴样细胞和外周记忆性CD4 T细胞的再激活、转运和功能中的作用。所提出的实验结果将为同种异体移植排斥反应中同种反应性记忆CD4 T细胞的免疫生物学机制提供见解。这一信息将有助于开发联合疗法来改善同种异体移植物的功能和致敏患者的生存率。

DESCRIPTION (provided by applicant): 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 CD4 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 CD4 T cells affects their activation, function and susceptibility to lymphoid sequestration and to costimulatory blockade. We hypothesize that lymphoid but not peripheral memory CD4 T cells contribute to cardiac allograft rejection by providing help for the induction of donor-reactive CD8 T cells and alloantibody while peripheral memory CD4 T 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 of memory CD4 T cells and for the migration of both memory and newly generated effector T cells into the graft. To test this hypothesis, we propose to compare the migratory properties and functions of lymphoid versus peripheral memory CD4 T cells, to test the effect of lymphoid sequestration on the function of lymphoid versus 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 CD4 T 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.