Complement and T Cell Mediated Allograft Rejection

描述（由申请人提供）：补体系统，传统上被认为是先天免疫库的一部分，被认为是细胞介导的同种异体移植物损伤的调节剂。我们的小组进一步表明，旁路途径补体成分C3、因子D和因子B在同源相互作用期间由T细胞和APC产生和上调，并且补体调节分子衰变加速因子（decay accelerating factor，DAF）调节诱导的效应T细胞应答的强度。APC表达的补体的生理重要性通过以下发现而突出：在不存在补体的情况下T细胞免疫增强，这种增强是替代途径补体依赖性的，并且其通过施用抗C5 mAb而被部分抑制。这些观察结果背后的详细机制需要研究出来，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，伴随着通过CD 28/CD 80/86提供的共刺激信号，导致双方产生和释放旁路途径补体，并在T细胞：APC界面激活补体。局部产生的补体裂解产物，包括葡萄球菌毒素C3 a和C5 a，与T细胞和APC上的受体结合，并且部分地通过上调细胞因子分泌，作为必要的信号起作用以最佳地诱导效应T细胞的活化、扩增和分化并限制细胞凋亡。使用最先进的细胞免疫学、补体学和移植技术，我们将测试补体对同种异体反应性效应T细胞免疫诱导的调节作用的分子机制，2）测试骨髓细胞衍生的补体和补体是同种异体反应性T细胞免疫的必需调节剂的假设，3）确定对C3 a和/或C5 a及其受体的需求，C3 aR和C5 aR作为同种异体反应性T细胞免疫的调节剂，以及4）检验以下假设：局部产生和活化的旁路途径补体是同种异体反应性T细胞的CD 28诱导的共刺激的重要下游中间体。这些发现将为已知导致急性和慢性移植排斥反应的T细胞同种异体反应性生理学提供新的基本见解，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.