ENDOTHELIAL MODIFICATIONS THAT REDUCE T CELL ACTIVATION

减少 T 细胞激活的内皮修饰

• 批准号: 6490725
• 负责人: JORDAN S POBER
• 金额: $ 47.67万
• 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490725
• 关键词: CD2 molecule; CD40 molecule; SCID mouse; T lymphocyte; anergy; blocking antibody; cell adhesion molecules; cell cell interaction; homologous transplantation; human tissue; interleukin 10; interleukin 11; leukocyte activation /transformation; leukocyte adhesion molecules; skin transplantation; tissue /cell culture; transplant rejection; vascular endothelium

The investigators have previously shown that cultured human endothelial cells (EC) can activate allogeneic CD4+ and CD8+ T cells to secrete cytokines, display effector molecules (e.g., CD40L, FasL) and receptors (e.g., CD25, the IL-2Ralpha chain), and proliferate in response to IL-2. The response of T cells to cultured EC depends upon EC display of MHC molecules, of costimulators and of adhesion molecules. These observations have led to a two part hypothesis. First, the investigators propose that human EC in vascularized allografts can initiate rejection reactions. Second, that modifications to reduce expression or function of graft EC costimulators and/or adhesion molecules will reduce graft rejection. In the current application, they propose to extend their studies of the role of specific costimulator molecules (LFA-3 and CD40) and adhesion molecules (ICAM-1 and ICAM-2) on these and other early T cell responses (e.g., receptor ITAM, ZAP 70 and linker molecule phosphorylation, transcription factor activation, gene expression, and proliferation in primary and secondary cultures) in vitro. They also will examine the role of costimulators and adhesion molecules and of selected other proteins (e.g., gap junction proteins) in the formation of immune synapses between alloreactive T cells and EC. They will use established and develop new limiting dilution approaches to evaluate the extent of recognition of allogeneic EC by the direct and indirect (i.e., dendritic cell-dependent) pathways, evaluate the effects of immunoregulatory cytokines (IL-10 and IL-11) on these responses, and evaluate novel methods of acquiring and displaying alloantigens (e.g., membrane transfer or DNA incorporation from phagocytosed nuclei). Finally, they will extend their study of human EC-mediated activation of T cells to in vivo settings by examining the roles played by EC costimulators and adhesion molecules in huPBL-SCID mice chimeric animals engrafted with vascularized skin or with synthetic vessels formed with cultured human EC. The results of these studies may lead to new therapeutic strategies for allograft preservation and may also apply to other clinical settings where T cells interact with vascular endothelium, e.g., in atherosclerosis and receptors and acute coronary syndromes.

研究人员此前已证明，培养的人内皮细胞 (EC) 可以激活同种异体 CD4+ 和 CD8+ T 细胞分泌细胞因子，展示效应分子（例如 CD40L、FasL）和受体（例如 CD25、IL-2Rα 链），并响应 IL-2 进行增殖。 T 细胞对培养的 EC 的反应取决于 MHC 分子、共刺激物和粘附分子的 EC 展示。 这些观察结果得出了由两部分组成的假设。 首先，研究人员提出，血管化同种异体移植物中的人类 EC 可以引发排斥反应。 其次，减少移植物 EC 共刺激物和/或粘附分子的表达或功能的修饰将减少移植物排斥。 在当前的应用中，他们建议在体外扩展特定共刺激分子（LFA-3和CD40）和粘附分子（ICAM-1和ICAM-2）对这些和其他早期T细胞反应（例如受体ITAM、ZAP 70和接头分子磷酸化、转录因子激活、基因表达和原代和继代培养物增殖）的作用的研究。 他们还将研究共刺激剂和粘附分子以及选定的其他蛋白质（例如间隙连接蛋白）在同种异体反应性 T 细胞和 EC 之间免疫突触形成中的作用。 他们将使用已建立和开发的新的有限稀释方法来评估直接和间接（即树突细胞依赖性）途径对同种异体 EC 的识别程度，评估免疫调节细胞因子（IL-10 和 IL-11）对这些反应的影响，并评估获取和展示同种异体抗原的新方法（例如，膜转移或 DNA 掺入） 被吞噬的细胞核）。 最后，他们将通过检查 EC 共刺激剂和粘附分子在移植有血管化皮肤或由培养的人类 EC 形成的合成血管的 huPBL-SCID 小鼠嵌合动物中所发挥的作用，将人类 EC 介导的 T 细胞激活的研究扩展到体内环境。 这些研究的结果可能会带来同种异体移植物保存的新治疗策略，也可能适用于 T 细胞与血管内皮相互作用的其他临床环境，例如动脉粥样硬化和受体以及急性冠状动脉综合征。