This proposal targets endothelial cell (EC) biology in leukocyte trafficking and inflammation, focusing on the role of vascular adhesion receptors and activating factors in the control of lymphocyte homing. We have shown that vascular signaling through Galphai protein-linked receptors triggers integrin-dependent lymphocyte arrest in high endothelial venules in lymph nodes and Peyer's patches. The hypothesis is that vascular triggering of lymphocyte integrins is mediated by the emerging family of chemoattractant cytokines, and that these chemokines help control lymphocyte-EC recognition and hence lymphocyte recruitment in a site, inflammatory state, and lymphocyte subset-selective fashion. 1) The ability of novel chemokines to induce rapid ICAM-dependent adhesion of blood-borne naive and memory lymphocyte subsets, and to trigger their arrest under physiologic shear will be explored. Responding lymphocyte subsets will be identified by patterns of differentiation antigen, cytokine, and especially homing receptor expression. 2) The investigator will explore the hypothesis that chemokines can differentially activate lymphocyte beta2 vs. alpha4 integrins, thus providing a novel level of vascular control of leukocyte adhesion and recruitment. 3) The involvement of proadhesive chemokines in EC-triggered lymphocyte adhesion and arrest will be assessed in physiologic models. Antibodies to target chemokines will be used a) to assess in immunohistologic studies their display by vascular endothelium, and hence their availability for participation in physiologic adhesion-triggering responses; and b) to explore their physiologic importance in in vivo homing and in situ videomicroscopic studies of lymphocyte-EC interactions. He will focus initially on hypothesized involvement of high endothelial venule-associated 6Ckine and/or MIP3beta in lymphocyte homing to secondary lymphoid tissues in vivo. 4) Receptor(s) for chemokines implicated in vascular arrest of lymphocytes will be identified, and antibodies against them will be used to characterize their involvement in endothelial interactions and lymphocyte homing into lymphoid tissues and/or sites of inflammation. Finally, in a continuation of earlier Aims, he will 5) evaluate the phenotype of MAdCAM-1-deficient mice. The proposed studies should expand our understanding of the critical role of the vascular endothelium in regulating lymphocyte trafficking during normal and pathologic immune responses.
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