Movement of Recipient T-Cells Away From an Allograft

描述（由申请人提供）：实现长期网站的目标- 对同种异体组织特异性耐受或供体特异性无反应 而不需要联合全身免疫抑制， 从死亡率和发病率来看， 与同种异体移植排斥反应有关。迄今为止， 急性和慢性移植物排斥主要是通过 针对活化受体功能的免疫抑制剂 异型抗原特异性T 细胞 临床受益 这些系统 免疫抑制治疗是以增加的发病率为代价的， 危及生命的机会性感染和移植相关 恶性肿瘤。已经开发了新的免疫抑制剂， 通过中断参与排斥反应的分子事件来干扰排斥反应， 直接和间接识别同种异体抗原，从而诱导耐受 使用用供体抗原预处理受体和 继续 1 1 R21 AI49858-01 3 Sep 作者声明：Mark C. 短期免疫抑制或免疫调节治疗。其他新颖 诱导供体特异性对同种异体移植物无反应性的靶点 已提出的措施，包括禁止贩运或 受体免疫细胞迁移到同种异体移植物中。我们最近 发现了一种新的生物学机制，我们称之为趋化性， 它被定义为免疫细胞主动迁移离开一个 趋化因子 特别是，我们已经确定了几个化学动力学因子， 包括趋化因子，基质细胞衍生因子-1（SDF-1）， 体外人T细胞的趋化反应和消除T细胞 迁移到特定的解剖部位，以响应抗原攻击， 小鼠体内模型。此外，我们已经证明，高水平的 由人骨髓和胸腺基质产生的SDF-1有助于 在体内从这些解剖空间排除成熟T细胞。 我们 假设趋化因子的组成型表达， 同种异体移植组织对T细胞的趋化反应可以 导致从同种异体移植物中排除受体免疫效应细胞。 这将为同种异体移植物创造一个免疫特权位点， 一种全新的方法，通过这种方法， 在体内诱导和防止移植物排斥。 该应用程序有两个 具体目的：1）鉴定CXC和CC型趋化因子， 从活化的T细胞引发趋化反应。迁徙 与移植物排斥反应相关的T细胞亚群的体内反应 将使用一组体外迁移测定来定量。2)的 开发小鼠模型以定量 诱导趋化反应的趋化因子的表达 活化的受体T细胞在预防或消除移植物排斥中的作用 vivo. 该应用程序代表 第一步， 使用 在新的治疗方法中诱导长期存在的趋化剂 位点特异性的功能耐受，通过引起 同种异体抗原特异性受体免疫迁移 效应细胞进入 同种异体器官移植 实现本报告提出的目标 最终有助于预防急性和慢性移植物 排斥和最大限度地减少合并治疗的需要 全身性免疫抑制剂的移植受者。

DESCRIPTION (provided by applicant): The goal of achieving longstanding site- specific tolerance or donor-specific unresponsiveness to allogeneic tissue without the need for combined systemic immune-suppression is of clinical importance in transplantation medicine in view of the mortality and morbidity associated with rejection of an allograft. To date therapeutic control over both acute and chronic graft rejection has been achieved predominantly with immunosuppressive agents targeted against the function of activated recipient alloantigen-specific T cells. The clinical benefit of these systemic immunosuppressive therapies is achieved at the cost of an increased incidence of life threatening opportunistic infections and transplantation associated malignancies. Novel immunosuppressive agents have been developed which attempt to interfere with rejection by interrupting molecular events involved in the direct and indirect recognition of alloantigens and thereby inducing tolerance using the combination of pretreatment of the recipient with donor antigen and Continued 1 1 R21 AI49858-01 3 SEP Poznansky, Mark C. a short course of immune suppressive or immunomodulatory therapy. Other novel targets for the induction of donor-specific unresponsiveness to allogeneic tissue have been proposed and include the suppression of the trafficking or migration of recipient immune cells into the allograft. We have recently identified a novel biological mechanism, which we have termed chemofugetaxis, and which is defined as the active migration of immune cells away from a chemokine. In particular, we have identified several chemokinetic factors, including the chemokine, stromal-cell derived factor-1 (SDF-1), which elicit a chemofugetactic response from human T cells in vitro and abrogate T-cell migration into a specific anatomic site in response to an antigen challenge in a murine model in vivo. In addition, we have demonstrated that a high level of SDF-1 generated by human bone marrow and thymus stroma contributes to the exclusion of mature T cells from these anatomical spaces in vivo. We hypothesize that the constitutive expression of a chemokine that elicits a chemofugetactic response from T cells by allogeneic transplanted tissue could lead to the exclusion of recipient immune effector cells from the allograft. This would create an immune privileged site for the allograft and represent an entirely novel method by which longstanding site-specific tolerance could be induced and graft rejection prevented in vivo. The application has two specific aims: 1) The identification of CXC- and CC-type chemokines that elicit a chemofugetactic response from activated T cells. The migratory responses of subpopulations of T cells relevant to graft rejection in vivo would be quantitated using a battery of in vitro transmigration assays. 2) The development of a murine model to quantitate the effectiveness of the expression of a chemokine that elicits a chemofugetactic response from activated recipient T cells in preventing or abrogating graft rejection in vivo. This application represents the first step toward the use of chemofugetactic agents in a novel therapeutic approach to induce longstanding site-specific functional tolerance by causing the long-term reversal of the migration of alloantigen-specific recipient immune effector cells into transplanted allogeneic organs. The achievement of the goals presented herein could ultimately contribute to the prevention of acute and chronic graft rejection and the minimization of the need for concomitant treatment of transplant recipients with systemic immunosuppressive agents.