ENDOTHELIAL MODIFICATIONS THAT REDUCE T-CELL ACTIVATION

减少 T 细胞激活的内皮修饰

• 批准号: 2227379
• 负责人: JORDAN S POBER
• 金额: $ 34.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2227379
• 关键词: SCID mouse; antisense nucleic acid; blocking antibody; cytotoxic T lymphocyte; helper T lymphocyte; homologous transplantation; human subject; interleukin 2; leukocyte activation /transformation; lymphocyte proliferation; monoclonal antibody; skin transplantation; transplant rejection; vascular endothelium

DESCRIPTION (Adapted from the investigator's abstract):The previous work has demonstrated that human endothelial cells (EC) can activate allogeneic T lymphocytes to secrete IL-2 and to proliferate.The EC signals involved in triggering T cell activation include expression both of cytokine-inducible class I and class II major histocompatibility complex (MHC) molecules (for activation of CD8+ and CD4+ T cells, respectively) and of membrane "costimulator" molecules, including LFA-3 (CD58) and as yet unidentified proteins. In this application, they propose to use monoclonal antibody blocking strategies to identify additional molecules involved in CD4+ and CD8+ T cell activation by allogenic EC and then to optimize conditions for reducing the expression of such molecules, using antisense oligonucleotides, retrovirus encoded antisense RNA, primary amines or "decoy" promoter oligonucleotides. They will test such modified EC in four established in vitro assays of lymphocyte activation to determine if the ability to activate T cells is correspondingly reduced.Specifically, they will assay: T cell proliferation induced by allogenic EC; T cell IL-2 production induced by allogeneic EC; limiting dilution analysis of T cell IL-2 production induced by allogenic EC; and EC-mediated costimulation of T cell IL-2 production induced by phytohemagglutinin. They will examine EC in human skin or in synthetic vascular networks that have been transplanted into SCID mice previously or subsequently reconstituted with a human immune system, to test for the ability of EC to activate T cells in vivo. Finally, this model will be used to determine whether modified EC have reduced ability to cause T cell activation and immune-mediated injury in vivo, assessed by high resolution morphologic techniques. These experiments could serve as a new approach to reducing immune-mediated injury, and may open new approaches for EC transplantation.

描述（改编自研究者摘要）：先前的工作 已经证明人内皮细胞（EC）可以激活 同种异体T淋巴细胞分泌IL-2和增殖。EC 参与触发T细胞活化的信号包括表达 主要组织相容性I类和II类 复合物（MHC）分子（用于活化CD 8+和CD 4 + T细胞， 和膜“共刺激分子”，包括LFA-3 （CD 58）和尚未鉴定的蛋白质。 在本申请中，它们 建议使用单克隆抗体阻断策略来识别 参与CD 4+和CD 8 + T细胞活化的其他分子 同种异体EC，然后优化降低表达的条件 使用反义寡核苷酸，逆转录病毒编码的 反义RNA、伯胺或“诱饵”启动子寡核苷酸。 他们 将在四个已建立的体外试验中测试这种修饰的EC， 淋巴细胞活化，以确定活化T细胞的能力是否 具体来说，他们将检测：T细胞 同种异体EC诱导的增殖;诱导的T细胞IL-2产生 通过同种异体EC; T细胞IL-2产生的有限稀释分析 同种异体EC诱导的T细胞IL-2的表达以及EC介导的T细胞IL-2共刺激 由植物血凝素诱导产生。 他们将在人体内检测EC 皮肤或人造血管网络中， 先前或随后用人类免疫重建的SCID小鼠 系统，以测试EC在体内活化T细胞的能力。 最后，该模型将用于确定修改后的EC是否具有 导致T细胞活化和免疫介导损伤的能力降低 在体内，通过高分辨率形态学技术评估。 这些 实验可以作为一种新的方法来减少免疫介导的 损伤，并可能为EC移植开辟新途径。