This is a new application that proposes to study regulation of chemokine receptor expression by cytokines in experimental granulomas, and to evaluate the contributions of these various receptors to the granulomatous response. The PI previously developed a novel murine model of synchronized T cell-mediated granuloma formation using agarose beads coated with either mycobacterial or schistosomal antigens to elicit the formation of lesions that show type 1 or type 2 cytokine responses, respectively. These studies demonstrated that cytokine and chemokine receptor expression differ in the two distinct granulomata. The experiments proposed here will extend previous studies which examined the contribution of selected cytokines to the development of granulomas in vivo.
In Aim 1, flow cytometry and RT-PCR will be used to define the profiles of chemokine receptor expression in leukocyte populations during the course of granuloma development.
Aim 2 will characterize granuloma formation in chemokine receptor knockout mice.
Aim 3 will attempt to determine the roles of selected cytokines in regulating chemokine receptor expression during granuloma formation, using cytokine knockout mice or anti-cytokine antibodies. Lastly, in Aim 4, the PI will attempt to manipulate granuloma formation in vivo by administering chemokines, and truncated chemokines that function as receptor antagonists, via osmotic pumps.
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