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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026551-02
Application #
3140319
Study Section
Immunobiology Study Section (IMB)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Ulich, T R; Yi, E S; Yin, S et al. (1993) Hematologic effects of stem cell factor alone and in combination with G-CSF and GM-CSF in vivo and in vitro in rodents. Int Rev Exp Pathol 34 Pt A:215-33
Yi, E S; Ulich, T R (1992) Endotoxin, interleukin-1, and tumor necrosis factor cause neutrophil-dependent microvascular leakage in postcapillary venules. Am J Pathol 140:659-63
Ulich, T R; del Castillo, J; Yi, E S et al. (1991) Hematologic effects of stem cell factor in vivo and in vitro in rodents. Blood 78:645-50
Ulich, T R; Guo, K Z; Remick, D et al. (1991) Endotoxin-induced cytokine gene expression in vivo. III. IL-6 mRNA and serum protein expression and the in vivo hematologic effects of IL-6. J Immunol 146:2316-23
Ulich, T R; del Castillo, J (1991) The hematopoietic and mature blood cells of the rat: their morphology and the kinetics of circulating leukocytes in control rats. Exp Hematol 19:639-48
Ulich, T R; Yin, S; Guo, K et al. (1991) Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation. Am J Pathol 138:1097-101
Ulich, T R; del Castillo, J; McNiece, I K et al. (1991) Stem cell factor in combination with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF synergistically increases granulopoiesis in vivo. Blood 78:1954-62
Ulich, T R; del Castillo, J; Yin, S M et al. (1991) The erythropoietic effects of interleukin 6 and erythropoietin in vivo. Exp Hematol 19:29-34
Ulich, T R; Watson, L R; Yin, S M et al. (1991) The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS-, IL-1-, and TNF-induced inflammatory infiltrate. Am J Pathol 138:1485-96
Ulich, T R; Yin, S M; Guo, K Z et al. (1991) The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation. Am J Pathol 138:521-4

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