Complement and T Cell Mediated Allograft Rejection

描述(由申请人提供)：补体系统，传统上被认为是天然免疫系统的一部分，被认为是细胞介导的同种异体移植损伤的调节器。我们的研究小组进一步证明，替代途径补体成分C3、D因子和B因子在同源相互作用中由T细胞和APC产生和上调，补体调节分子衰变加速因子(DAF)调节诱导效应T细胞反应的强度。APC表达的DAF在没有DAF的情况下T细胞免疫增强，这种增强是补体依赖的替代途径，并被抗C5单抗部分抑制，这一发现突出了APC表达的DAF的生理重要性。这些观察结果背后的详细机制需要确定，启动补体成分产生的信号需要确定，特别是在移植的背景下。我们的初步结果支持以下假设：同种异体反应性T细胞和APC之间的同源相互作用伴随着CD28/CD80/86提供的共刺激信号，导致双方产生和释放替代途径补体，并在T细胞：APC界面激活补体。局部产生的补体裂解产物，包括过敏毒素C3a和C5a，与T细胞和APC上的受体结合，部分通过上调细胞因子分泌，作为必要的信号最佳地诱导效应T细胞的激活、扩增和分化，并限制细胞凋亡。利用最先进的细胞免疫学、互补学和移植技术，我们将测试补体对诱导同种异体反应性T细胞免疫的调节作用的分子机制，2)检验骨髓细胞来源的补体和DAF是同种异体反应性T细胞免疫的基本调节器的假设，3)确定对C3a和/或C5a及其受体的需求，C3aR和C5aR作为同种异体反应性T细胞免疫的调节剂，以及4)检验局部产生和激活的替代途径补体是CD28诱导的同种异体反应性T细胞共刺激的重要下游介质的假说。这些发现将为T细胞同种异体反应的生理学提供新的基本见解，已知的T细胞同种异体反应会导致急性和慢性移植排斥反应，并可能为治疗这些疾病提供新的治疗靶点。

DESCRIPTION (provided by applicant): The complement system, traditionally considered part of the innate immune repertoire has been implicated as a modulator of cell mediated allograft injury. Our group has further shown that alternative pathway complement components C3, factor D and factor B are produced and upregulated by T cells and by APCs during cognate interactions, and that a complement regulatory molecule, decay accelerating factor (DAF), modulates the strength of induced effector T cell responses. The physiologic importance of APC-expressed DAF is highlighted by the findings that T cell immunity is enhanced in the absence of DAF, this augmentation is alternative pathway complement dependent, and it is partially inhibited by administration of an anti-C5 mAb. Detailed mechanisms underlying these observations need to be worked out and signals initiating complement component production need to be determined, particularly in the context of transplantation. Our preliminary results support the following hypothesis: Cognate interactions between alloreactive T cells and APCs accompanied by costimulatory signals provided through CD28/CD80/86 results in production and release of alternative pathway complement by both partners, and complement activation at the T cell: APC interface. The locally produced complement split products, including anaphylotoxins C3a and C5a, bind to receptors on T cells and APCs, and in part, through upregulating cytokine secretion, function as requisite signals to optimally induce activation, expansion and differentiation of effector T cells and to limit apoptosis. Using state of the art cellular immunology, complementology and transplantation techniques we will test the molecular mechanisms underlying complement's modulatory effects on induction of alloreactive effector T cell immunity, 2) test the hypothesis that bone marrow cell derived complement and DAF are essential modulators of alloreactive T cell immunity, 3) determine the requirement for C3a and/or C5a and their receptors, C3aR and C5aR as modulators of alloreactive T cell immunity, and 4) test the hypothesis that locally produced and activated alternative pathway complement is an essential downstream intermediary of CD28-induced costimulation for alloreactive T cells. The findings will provide new basic insight into the physiology of T cell alloreactivity that is known to lead to acute and chronic transplant rejection and will potentially provide novel therapeutic targets to treat these diseases.