The T to Mo component of the cellular immune response is characterized in part by T cell induction of the biosynthesis and secretion by monocytes of a variety of molecules which mediate inflammation. On antigen-specific stimulation, T cells release soluble factors which act on cells of the monocyte/macrophage lineage to induce transcription of a set of genes which includes those encoding molecules mediating Mo effector functions. Among the various Mo effector functions which are so induced and regulated is that of cellular cytotoxicity, a fundamental inflammatory response which under appropriate conditions includes cytostasis or cytolysis of tumor cells. In monocytes (Mo) that have been """"""""primed"""""""" by interferon gamma in the absence of endotoxin, tumoricidal cellular cytotoxicity can be elicited by a novel 55 kd lymphokine """"""""second signal"""""""" of T cell origin that we have designated Cytotoxicity Triggering Factor (CTF). CTF triggers tumoricidal cellular cytoxicity in """"""""primed"""""""" Mo by inducing the synthesis of tumor necrosis factor (TNF alpha), which mediates this activity on TNF alpha-susceptible tumor cells. We propose to first clone cDNA encoding human CTF directly by transient expression in COS cells, and to then over-express, isolate, and characterize the recombinant CTF protein, to isolate and characterize the natural CTF protein(s) made by T cells, and finally to characterize the immunobiology of CTF, including the role of CTF in the host's immune response to tumors. In particular, we will examine the hypothesis that tumor-associated macrophages can be selectively triggered by CTF in vivo as a result of prior in situ priming, thus permitting in situ induction of biologically effective tumoricidal activity without the systemic effects of TNF alpha.
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