The purpose of this proposal is to continue to study the mechanism of cellular immunity and hypersensitivity with the hope of finding ways to modulate this immune response in relevant clinical states. The focus is on lymphokines that alter the behavior of macrophages and activate them. We propose: to obtain purified and characterized lymphokines using T-T cell hybrids and recombinant DNA technology; to study the basis for heterogeneity of lymphokines and their interrelationship; to characterize the macrophage receptors for these; and to study the cellular and genetic changes associated with alteration of macrophage function by lymphokines. The projects to attain these goals are: 1) Continue to generate a series of human T-T cell hybrids which secrete MIF and MAF and to purify and characterize these. In addition, generate monoclonal antibodies to MIF and MAF and develop an improved assay for human MAF. 2) Further studies on the macrophage activating factor which enhances anti-viral activity in human macrophages and which has no interferon activity, and study a lymphokine which induces leucotriene production in human macrophages. 3) Examination of the basis and biological significance of the heterogeneity of MIF and MAF induced by antigens such as bacteria, fungi and viruses, and the production of lymphokines by different subsets of lymphocytes. 4) Identification of genes coding for MIF and MAF, the characteristics of these genes and the production of recombinant MIF and MAF. 5) Further studies on the human macrophage receptor for MIF: characterization, binding kinetics and biology, and the analysis of the fate of the labeled receptor and ligand by light and electron microscopy. 6) HL60 cells as a model for macrophage response to MIF. The addition of the MIF glycolipid receptor to these cells makes them responsive to MIF. The molecular events that follow stimulation by the lymphokine will be analyzed.
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