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.