Movement of Recipient T-Cells Away From an Allograft

受体 T 细胞远离同种异体移植物的运动

• 批准号: 6534341
• 负责人: MARK Coleman POZNANSKY
• 金额: $ 25.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534341
• 关键词: T cell receptor; biological models; cell migration; chemokine; cytokine receptors; flow cytometry; fluorescent dye /probe; helper T lymphocyte; homologous transplantation; human tissue; immune tolerance /unresponsiveness; immunosuppression; isoantigen; laboratory mouse; model design /development; monocyte; suppressor T lymphocyte; tissue /cell culture; transplant rejection; transplantation immunology; video microscopy

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.

描述（由申请人提供）：实现长期存在的位点特异性或对同种异体组织的供体特异性无反应的目的 无需结合全身免疫抑制是临床 鉴于死亡率和发病率，移植医学的重要性 与拒绝同种异体移植有关。迄今为止的治疗控制 急性和慢性移植的拒绝均主要是通过 针对激活受体功能的免疫抑制剂 同种抗原特异性T细胞。 这些系统性的临床益处 以增加发病率的代价实现了免疫抑制疗法 威胁生命的机会性感染和移植 恶性肿瘤。已经开发了新颖的免疫抑制剂 通过中断涉及的分子事件来干扰排斥 直接和间接识别同种抗原，从而引起公差 使用接受者预处理与供体抗原和 持续 1 1 R21 AI49858-01 3月3日 Poznansky，Mark C. 短暂的免疫抑制或免疫调节疗法。其他小说 诱导供体特异性无反应性的目标 已经提出了组织，包括抑制贩运或 受体免疫细胞迁移到同种异体移植中。我们最近有 确定了一种新型的生物学机制，我们称之为化学法曲霉， 并将其定义为免疫细胞的主动迁移 趋化因子。 特别是，我们已经确定了几种趋化因子， 包括趋化因子，基质细胞衍生因子-1（SDF-1），它引起a 人类T细胞的化学法属反应在体外和废除T细胞T细胞 响应于抗原挑战的特定解剖部位迁移到特定的解剖部位 体内的鼠模型。此外，我们已经证明了高水平 人骨髓和胸腺基质产生的SDF-1有助于 在体内这些解剖空间中排除成熟的T细胞。 我们 假设趋化因子的本构表达引起A 通过同种异体移植组织从T细胞中的化学法属反应可以 导致从同种异体移植中排除受体免疫效应细胞。 这将为同种异体移植物创建一个免疫特权网站，并代表 长期以来特定地点的容忍度的完全新颖的方法 诱导和移植抑制阻止了体内。 该应用程序有两个 具体目的：1）CXC-和CC型趋化因子的鉴定， 引起活化T细胞的化学反应。迁徙 与体内移植排斥相关的T细胞亚群的反应 将使用一系列体外透射测定法进行定量。 2） 开发鼠模型以量化的有效性 趋化因子的表达引起了从 激活的受体T细胞预防或废除移植物排斥 体内。 此应用程序是迈向使用的第一步 在一种新型治疗方法中，化学法型剂诱导长期 通过导致长期逆转的特定地点功能耐受性 同种抗原特异性受体免疫效应细胞迁移到 移植的同种器官。 实现此处提出的目标 最终可能有助于预防急性和慢性移植 排斥和最小化伴随治疗的需求 具有全身免疫抑制剂的移植受者。