Lymphotoxin (LT), a product of activated T cells, kills many cell types including several tumors and activated T cells. This effect may contribute significantly to tumor surveillance and may also regulate the immune response. LT, and the functionally and structurally related molecule, tumor necrosis factor (TNF), may also be involved in the pathogenesis of disease, paticularly those of autoimmune etiology. LT and TNF have non cytotoxic effects on various other target cells. These include activation of polymorphonuclear leukocytes and induction of monocyte differentiation. The goal of the project outlined here is to elucidate the mechanism of LT's pleiotropic effects and to understand the basis of its cytotoxic effects on some cells and its induction of differentiation in others. First the mechanism of LT's cytotoxic effects will be probed. Recombinant derived murine LT, biosynthetically labeled naturally derived LT and TNF, and LT peptides will be analyzed for receptor binding, effects on lysosomes, changes in intracellular calcium and arachidonic acid metabolism, and induction of nuclear changes, especially DNA fragmentation. The effect of murine LT on monocyte differentiation will be studied with murine monocyte tumors. Once such a system has been established, the mechanism of LT induction of differentiation will be studied and compared with its mechanism of killing. These studies on the systematic analysis of the mechanisms of LT's effects will provide information which will allow its optimal use as an immunotherapeutic agent. They will also provide insight into methods to inhibit these effects when they contribute to disease pathogenesis.
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