DISTINCT EFFECTS OF TRANSMEMBRANE AND SOLUBLE FAS LIGAND

描述：(改编自《调查者摘要》)： 最近的研究清楚地表明，效应性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，进行细胞凋亡。Fas/FasL 相互作用似乎在监管中至关重要。 小鼠自身反应性淋巴细胞缺乏这两种基因 Fas或FasL发展成严重的全身性自身免疫性疾病。基于 FasL强大的细胞毒作用，据预测，实验性 修改组织以结构性表达FasL将增强 将这些组织植入同种异体宿主体内。然而，在几个 系统，出于未知原因，FasL的表达不能保护组织 而是引发炎症反应。这个 当前的应用程序试图通过测试 以下工作假说：FasL活性的凋亡方面是 均由膜结合的FasL(MFasL)介导；相比之下， 炎症方面的FasL活性可归因于可溶性 FasL的一种形式(SFasL)，既能吸引又能激活 中性粒细胞，从而引发炎症。这一假设将是 通过以下具体目的进行检测：(1)比较mFasL和mFasL SFasL刺激中性粒细胞趋化能力的研究 和激活；(2)监测肿瘤细胞系的植入 接种后结构性表达mFasL或sFasL 同种或同基因宿主；以及(3)分析功能 一种小鼠品系T细胞的特性 非切割形式的mFasL。如果这一工作假设是正确的，那么 MFasL保护组织，而sFasL诱导炎症，这些研究 对促进器官移植有直接的临床意义 恶性肿瘤的移植和基因靶向。

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.