Induction of T Cell Chemoattractants in Acute Rejection

急性排斥反应中 T 细胞趋化剂的诱导

• 批准号: 6630853
• 负责人: Robert L Fairchild
• 金额: $ 33.53万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630853
• 关键词: T cell receptor; chemoattractants; chemokine; chemotaxis; cytokine receptors; disease /disorder model; flow cytometry; genetically modified animals; heart transplantation; helper T lymphocyte; homologous transplantation; immunocytochemistry; isoantigen; laboratory mouse; ligands; protein structure function; receptor binding; receptor expression; suppressor T lymphocyte; transplant rejection

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.

描述（由申请人提供）： 急性同种异体移植排斥仍然是移植中的一个重要问题，它破坏了用于治疗终末期器官疾病的移植物的功能和存活。 急性排斥反应是由同种异体抗原引发的 T 细胞的协调浸润和效应功能介导的，导致移植组织遭到破坏。 引导 T 细胞进入同种异体器官移植物的因素仍不清楚。 我们的研究表明，在急性排斥反应的过程中，皮肤和心脏同种异体移植物中会暂时诱导趋化细胞因子、趋化因子。 在这些模型以及临床心脏移植的活检中发生急性排斥反应时，存在高水平的几种趋化因子，包括 IFN-γ 诱导的趋化因子 Mig（一种有效的 T 细胞趋化剂）。 Mig 特异性抗体的施用可抑制 T 细胞浸润到同种异体皮肤移植物中，并促进移植物的长期存活，支持在移植中使用该策略。 我们使用同种异体心脏移植模型进行的初步研究表明，接受 Mig 特异性抗体的治疗可延迟 T 细胞浸润和移植物的急性排斥反应，但移植物最终会被排斥。 这种延迟排斥不是通过 Mig 定向将 T 细胞募集到同种异体移植物中来介导的。 在此应用中，我们将使用小鼠模型测试趋化因子受体的诱导和作用，该受体引导同种异体抗原引发的 T 细胞浸润到同种异体心脏移植物中，以及 T 细胞趋化剂 Mig 在血管化心脏同种异体移植物急性排斥过程中的作用。 在具体目标 1 中，我们将测试在心脏同种异体移植物启动过程中趋化因子受体在个体和可识别的同种异体抗原特异性 T 细胞群上的时间表达。 具体目标 2 将测试这些受体在引导同种异体抗原引发的 CD4+ 和 CD8+ T 细胞进入同种异体移植物中的作用，使用受体缺陷小鼠作为受体。 具体目标 3 将测试 Mig 在引导同种异体抗原引发的 T 细胞进入同种异体移植物中的作用。 具体目标 4 将测试介导接受 Mig 特异性抗体治疗的受者心脏同种异体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阐明急性排斥反应期间 T 细胞募集到同种异体移植物中的机制。 这些结果应该支持新型治疗试剂和策略的开发，以抑制 T 细胞募集到同种异体移植物中，提高实体器官同种异体移植物的存活率，同时减少对目前使用的普遍且使人衰弱的免疫抑制方案的依赖。