DISTINCT EFFECTS OF TRANSMEMBRANE AND SOLUBLE FAS LIGAND

跨膜和可溶性 FAS 配体的不同作用

• 批准号: 2736955
• 负责人: Ann Marshak-Rothstein
• 金额: $ 8.52万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2736955
• 关键词: CD95 molecule; T lymphocyte; apoptosis; chemotaxis; inflammation; laboratory mouse; leukocyte activation /transformation; ligands; neutrophil; tissue /cell culture; transplantation immunology

DESCRIPTION: (Adapted from Investigator's abstract): Recent studies have clearly shown that effector T-cells expressing the membrane protein Fas-ligand (FasL) can induce target cells expressing the appropriate receptor, Fas, to undergo apoptosis. Fas/FasL interactions appear to be of paramount importance in the regulation of autoreactive lymphocytes since mice deficient in expression of either Fas or FasL develop severe systemic autoimmune disease. Based on the potent cytotoxic effects of FasL, it was predicted that experimental modification of tissues to constitutively express FasL would enhance the engraftment of these tissues in allogeneic hosts. However, in several systems, for unknown reasons, FasL expression does not protect tissues from the immune system but instead induces an inflammatory response. The current application seeks to address this dichotomy by testing the following working hypothesis: The apoptotic aspects of FasL activity are all mediated by membrane-bound FasL (mFasL); in contrast, the inflammatory aspects of FasL activity can be attributed to the soluble form of FasL (sFasL) which serves to both attract and activate neutrophils and thus provoke inflammation. This hypothesis will be tested by means of the following specific aims: (1) comparing mFasL and sFasL with regard to their ability to stimulate neutrophil chemotaxis and activation; (2) monitoring the engraftment of tumor lines that constitutively express either mFasL or sFasL subsequent to inoculation of allogeneic or syngeneic hosts; and (3) analyzing the functional properties of T-cells from a mouse strain which can only express a noncleavable form of mFasL. If this working hypothesis is correct, and mFasL protects tissues while sFasL induces inflammation, these studies would have direct clinical relevance to enhancing engraftment of organ transplants and gene targeting of malignant tumors.

描述：（改编自研究者的摘要）： 最近的研究清楚地表明，效应 T 细胞表达 膜蛋白Fas配体（FasL）可诱导靶细胞表达 适当的受体Fas，经历细胞凋亡。 Fas/FasL 相互作用似乎对于监管至关重要 自身反应性淋巴细胞，因为小鼠缺乏任一表达 Fas 或 FasL 会导致严重的全身性自身免疫性疾病。基于 FasL 的强效细胞毒作用，据预测，实验 修饰组织以组成型表达 FasL 将增强 将这些组织植入同种异体宿主中。然而，在几个 系统中，由于未知原因，FasL 表达不能保护组织 来自免疫系统，而是诱导炎症反应。这 当前的应用程序试图通过测试来解决这种二分法 以下工作假设：FasL 活性的细胞凋亡方面是 全部由膜结合 FasL (mFasL) 介导；相比之下， FasL 活性的炎症方面可归因于可溶性 FasL (sFasL) 形式，具有吸引和激活作用 中性粒细胞，从而引发炎症。这个假设将是 通过以下具体目标进行测试：（1）比较 mFasL 和 sFasL 刺激中性粒细胞趋化性的能力 和激活； (2) 监测肿瘤细胞系的植入 接种后组成型表达 mFasL 或 sFasL 同种异体或同基因宿主； (3) 分析泛函 来自小鼠品系的 T 细胞的特性，该小鼠品系只能表达 mFasL 的不可切割形式。如果这个工作假设是正确的，并且 mFasL 保护组织，而 sFasL 诱导炎症，这些研究 与增强器官移植有直接的临床相关性 恶性肿瘤的移植和基因靶向。