DISTINCT EFFECTS OF TRANSMEMBRANE AND SOLUBLE FAS LIGAND

描述：（改编自研究者摘要）： 最近的研究清楚地表明，表达免疫调节因子的效应T细胞， 膜蛋白Fas配体（FasL）可诱导靶细胞表达Fas配体， 合适的受体Fas进行凋亡。FAS/FasL 互动似乎是最重要的监管， 自身反应性淋巴细胞，因为小鼠缺乏 Fas或FasL可发展为严重的系统性自身免疫性疾病。基于 FasL的强细胞毒性作用，预测实验 对组织进行组成型表达FasL的修饰将增强细胞的增殖， 这些组织在同种异体宿主中的移植。然而，在几个 系统，由于未知的原因，FasL表达并不保护组织 而是诱发炎症反应。的 本申请试图通过测试 以下工作假设：FasL活性的凋亡方面是 所有这些都是由膜结合FasL（mFasL）介导的;相反， FasL活性的炎症方面可归因于可溶性 FasL的形式（sFasL），其用于吸引和激活 中性粒细胞，从而引起炎症。这一假设将是 通过以下特定目的进行测试：（1）比较mFasL和 sFasL刺激中性粒细胞趋化性的能力 和活化;（2）监测肿瘤细胞系的植入， 在接种后组成型表达mFasL或sFasL 同种异体或同基因宿主的功能;和（3）分析功能性的 来自小鼠品系的T细胞的特性，该小鼠品系只能表达 mFasL的不可裂解形式。如果这个假设是正确的， mFasL保护组织，而sFasL诱导炎症，这些研究 将与增强器官移植直接相关 移植和恶性肿瘤的基因靶向。

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.