The specific aim is to test the hypothesis that the cytokines IL- 1 alpha and beta, TNF alpha and beta, and gamma-IFN play a role in the regulation of leukocyte trafficking and to determine the role of arachidonic acid metabolites as biochemical intermediates through which the cytokines exert their effects. Leukocyte trafficking is a complex phenomenon that is regulated at multiple steps in multiple tissues by a variety of cell types and soluble mediators. Leukocyte trafficking may be broadly defined as the rate of maturation of leukocytes in the bone marrow, the rate of release of leukocytes into the circulation, the regulation of the balance between marginated and freely circulating leukocytes, and the degrees of leukocytes from the circulation into lymphoid and nonlymphoid tissue under both physiologic and inflammatory conditions. The experimental design whereby the role of cytokines in leukocyte trafficking under physiologic and pathophysiologic conditions will be studied involves in vivo rat models in which the redistribution of leukocyte subsets will be kinetically quantitated in absolute numerical terms in the bone marrow, circulation, and tissues after intravenous administration of individual or combined cytokines. Extensive preliminary data from my laboratory has documented the usefulness of the rat models to be studied. The role of arachidonic acid metabolites as biochemical intermediates will be explored using inhibitors of arachidonate as biochemical intermediates will be explored using inhibitors or arachidonate metabolism. The significance of an understanding of the regulation of leukocyte trafficking is that mankind may acquire the ability to selectively direct leukocytes to act in a proinflammatory fashion (immunotherapy against infectious or neoplastic disease) or antiinflammatory fashion (amelioration or idiopathic or autoimmune inflammatory diseases). The results of initial clinical trials suggest that the effects of the cytokines to be studied on leukocyte trafficking will be virtually identical in humans and rats.
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