Movement of Recipient T-Cells Away From an Allograft

描述(由申请人提供)：实现对异体组织的长期耐受或供体特异性无反应的目标 不需要联合全身免疫抑制是临床上的 从死亡率和发病率看移植医学的重要性 与同种异体移植的排斥反应有关。迄今为止的治疗控制 急性和慢性移植物排斥反应主要是通过 针对激活受体功能的免疫抑制药 同种异体抗原特异性T细胞。这些全身性的临床益处 免疫抑制治疗是以增加发病率为代价的。 威胁生命的机会性感染和与移植相关的 恶性肿瘤。已经开发出新的免疫抑制剂，试图 通过阻断参与排斥反应的分子事件来干扰排斥反应 对同种异体抗原的直接和间接识别，从而诱导耐受 采用供体抗原和供体抗原联合预受体法 续 1 1 R21 AI49858-01 3 SEP 波兹南斯基，马克·C。 免疫抑制或免疫调节疗法的短疗程。其他小说 诱导供者特异性同种异体无反应的靶点 组织已经被提出，并包括制止贩运或 受体免疫细胞向同种异体移植物的迁移。我们最近做了 发现了一种新的生物学机制，我们称之为趋化轴， 它被定义为免疫细胞主动地从 趋化因子。特别是，我们已经确定了几个化学动力学因素， 包括趋化因子基质细胞衍生因子-1(SDF-1)，它能诱导 人T细胞体外趋化趋化反应及灭活T细胞 移行到特定的解剖部位以响应抗原挑战 一种体内的小鼠模型。此外，我们已经证明，高水平的 人骨髓和胸腺基质产生的SDF-1有助于 在体内将成熟的T细胞排除在这些解剖空间之外。我们 假设一种趋化因子的结构性表达可以引起 同种异体移植组织诱导T细胞趋化趋化反应 导致受体免疫效应细胞被排除在同种异体移植物之外。 这将为同种异体移植物创建一个免疫特权部位，并代表着 一种全新的方法，通过这种方法，长期存在的特定部位耐受性可以 体内诱导和预防移植物排斥反应。该应用程序有两个 具体目标：1)CXC和CC型趋化因子的鉴定 从激活的T细胞中引发趋化反应。迁徙的 移植排斥反应相关T细胞亚群的体内反应 将使用一组体外轮回试验进行定量。2) 小鼠模型的建立以量化治疗的有效性 趋化因子的表达及其诱导趋化反应的研究 活化的受体T细胞在预防或消除移植排斥反应中的作用 活着。此应用程序代表了使用 趋化性药物在一种新的治疗方法中的应用 部位特定的功能耐受性通过导致长期的 同种异体抗原特异性受体免疫效应细胞向 移植同种异体器官。实现本文件中提出的目标 可能最终有助于预防急性和慢性移植物 排斥反应和将同时治疗的需要降至最低 使用全身免疫抑制药的移植受者。

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.