The participation of lymphocytes in local immune or inflammatory responses depends in part on their ability to recognize and extravasate through specialized venules within lymphoid tissues and sites of chronic inflammation. Recent functional and molecular studies have demonstrated the existence of two independent lymphocyte-endothelial cell recognition systems mediating lymphocyte extravasation in peripheral lymph node and mucosal lymphoid tissues, systems thought to be critically important in the maintenance of mucosal immune specialization. Independent tissue-selective homing mechanisms have also been proposed for lymphocyte trafficking to extra-lymphoid sites of chronic inflammation, but, to date, definitive molecular proof of these putative homing specificities has not been published. This proposal is directed at identifying and characterizing such tissue- selective homing mechanisms in the setting of chronic inflammation, and the determination of the functional consequences of these mechanisms to the human inflammatory response. I have elected to focus on T-cell migration to inflamed skin because my preliminary work suggests that this tissue is likely a third lymphocyte homing specificity and site of tissue-specific immune specialization. These data indicate that skin-associated memory T- cells, both at cutaneous sites of chronic inflammation and circulating, can be specifically identified by their expression of a novel cell surface determinant, the Cutaneous Lymphocyte Associated antigen (CLA Ag), and that this T-cell subset may specifically extravasate at cutaneous inflammatory sites through an Endothelial-Leukocyte Adhesion Molecule-1 (ELAM-1)- dependent mechanism. To further characterize this proposed skin-selective homing specificity, my laboratory will initially focus on the structural and functional analysis of the CLA Ag, particularly the determination of whether this Ag represents the T-cell ELAM-1 ligand. If the CLA Ag proves to be the T-cell ELAM-1 ligand, we will use monoclonal antibodies to this molecule, to ELAM-1, and to other relevant adhesion molecule pairs (LFA- 1/ICAM-1, VLA-4/VCAM-1, LECCAM-1/PNAd) to determine the relative participation of these adhesion systems in T-cell binding to venules at cutaneous inflammatory sites. In parallel studies, we will 1) investigate the regulation of the CLA Ag and ELAM-1 binding ability in T-cell populations, particularly in regard to the characterization of skin-derived factors responsible for this regulation, 2) characterize the mechanisms responsible for preferential ELAM-1 expression on cutaneous venules in the setting of chronic inflammation, 3) functionally analyze the CLA Ag+ T-cell subset with the goal of identifying unique physiologic characteristics indicative of functional adaptation to the cutaneous microenvironment, and assess the involvement of skin-selective homing mechanisms in the pathogenesis of the skin-associated T-cell lymphoma mycosis fungoides. An understanding of the molecular basis and regulation of tissue-specific homing mechanisms will be critical in the understanding of inflammatory disease pathogenesis and lymphoma metastasis, and may lead to the development of highly selective modalities for the treatment of these disorders.
