With the exception of TNF and LT (both of which are secreted), members of the TNF family are membrane-associated T cell activation antigens, several of which are induced by IL-2. Receptors of these proteins (e.g. fas, CD40, the LT-beta receptor) are members of the TNF receptor family known primarily for their roles in B cell help (CD40), the induction of apoptosis (fas), or lymph node development (the LT-beta-R). Fas, CD40, and theLT-beta receptor have recently been demonstrated on the endothelium, where their functions are largely unknown. However, like the p55 TNF receptor, CD40 engagement has been shown to elicit adhesion molecule expression in these cells, thus raising the possibility that these TNF receptor family members may transmit signals upon contact with activated lymphocytes that are qualitatively similar to those induced by TNF itself. In addition to fas and the p55 TNF receptor, both CD40 and the LT-beta receptor were recently shown to transmit apoptotic signals in certain tumor cell lines, suggesting that they may play a role in tumor cell cytolysis mediated by IL-2-primed lymphocytes. The studies we have proposed in this application will assess the ability of IL-2 to induce the expression of membrane-associated TNF family members in various lymphoid populations in vitro and in vivo. The factors regulating the expression of their respective receptors (e.g. fas, CD40, the LT-beta receptor) on cultured endothelial cells and on skin and tumor-associated endothelium will also be determined. Several studies with tumor- bearing mice are proposed to assess the role played by the fas-L, CD40-L and 'membrane LT' present on IL-2-activated lymphocytes in IL-2-induced tumor regression and endothelial injury. Ultimately, these studies will address the feasibility of using fas-IgG, CD40-IgG, LT-beta receptor-IgG fusion proteins to attenuate the microvascular pathology resulting from the administration of IL-2.
