Induction of T Cell Chemoattractants in Acute Rejection

描述(由申请人提供)： 急性同种异体移植排斥反应仍然是移植中的一个重要问题，破坏了用于治疗终末期器官疾病的移植器官的功能和存活率。急性排斥反应是通过同种异体抗原免疫的T细胞的协同渗透和效应功能导致移植物组织的破坏而起作用的。引导T细胞进入同种异体器官移植的因素仍不明确。我们的研究表明，在急性排斥反应的进展过程中，皮肤和心脏移植中的趋化因子--趋化因子--的短暂诱导。在这些模型发生急性排斥反应时，以及在临床心脏移植的活检组织中，存在几种高水平的趋化因子，包括干扰素-γ诱导的趋化因子Mig，一种强大的T细胞趋化因子。给予Mig特异性抗体可抑制T细胞向同种异体皮肤移植物的渗透，并促进移植物的长期存活，支持在移植中使用这一策略。我们使用同种异体心脏移植模型的初步研究表明，使用Mig特异性抗体的受者治疗延迟了移植物的T细胞渗透和急性排斥反应，然而，移植物最终会被排斥。这种延迟排斥反应不是通过Mig直接将T细胞募集到同种异体移植物中来实现的。在这项应用中，我们将使用小鼠模型测试趋化因子受体的诱导和作用，这些受体引导同种异体抗原启动的T细胞渗透到心脏移植物中，以及T细胞趋化因子Mig在血管化心脏移植物急性排斥反应中的作用。在特定的目标1中，我们将测试趋化因子受体在个体和可识别的同种异体抗原特异性T细胞群上的瞬时表达。《特殊目的2》将以受体缺陷小鼠为受者，测试这些受体在引导同种异体抗原刺激的CD4+和CD8+T细胞进入同种异体移植物中的作用。特殊目标3将测试Mig在引导同种异体抗原诱导的T细胞进入同种异体移植物中的作用。特定目标4将测试在接受Mig特异性抗体治疗的受者中调节同种异体心脏移植延迟排斥反应的潜在机制。了解这些受体和Mig在急性排斥反应中的作用，将有助于阐明急性排斥反应期间T细胞向同种异体移植物募集的机制。这些结果应该支持开发新的治疗试剂和策略，以抑制T细胞向同种异体移植物的招募，提高实体器官移植物的存活率，同时减少对目前使用的普遍和衰弱的免疫抑制方案的依赖。

DESCRIPTION (provided by applicant): Acute allograft rejection remains a significant problem in transplantation, undermining the function and survival of grafts transplanted to treat end-stage organ disease. Acute rejection is mediated by the coordinated infiltration and effector functions of alloantigen-primed T cells resulting in destruction of the graft tissue. Factors directing T cells into organ allografts remain poorly defined. Our studies have demonstrated the temporal induction of chemoattractant cytokines, chemokines, in skin and heart allografts during the progression of acute rejection. At the time of acute rejection in these models as well as in biopsies from clinical heart transplants, high levels of several chemokines are present, including the IFN-gamma induced chemokine Mig a potent T cell chemoattractant. Administration of Mig-specific antibodies inhibits T cells infiltration into skin allografts and promotes long-term graft survival supporting the use of this strategy in transplantation. Our preliminary studies using a heart allograft model have indicated that recipient treatment with Mig-specific antibodies delays both T cell infiltration and acute rejection of the grafts, however, the grafts are eventually rejected. This delayed rejection is not mediated through Mig directed recruitment of T cells into the allograft. In this application we will test the induction and role of chemokine receptors that direct alloantigen-primed T cell infiltration into cardiac allografts and the role of the T cell chemoattractant Mig during acute rejection of vascularized heart allografts using a murine model. In Specific Aim 1 we will test the temporal expression of chemokine receptors on individual and identifiable alloantigen-specific T cell populations during priming to cardiac allografts. Specific Aim 2 will test the role of these receptors in directing the alloantigen-primed CD4+ and CD8+ T cells into allografts using receptor deficient mice as recipients. Specific Aim 3 will test the role of Mig in directing alloantigen-primed T cells into the allografts. Specific Aim 4 will test potential mechanisms mediating the delayed rejection of heart allografts in recipients treated with Mig-specific antibodies. Understanding the role of these receptors and Mig in acute rejection will elucidate mechanisms of T cell recruitment into allografts during acute rejection. The results should support the development of novel therapeutic reagents and strategies to inhibit T cell recruitment into allografts, improving solid organ allograft survival while decreasing the dependence on the generalized and debilitating immunosuppressive regimens currently in use.