Current Research and Scholarly Interests
We study the trafficking of white blood cells (lymphocytes, dendritic cells, monocytes, etc.), including their interactions with the endothelial lining of blood vessels at sites of leukocyte extravasation, and their chemotactic responses in tissues. These events regulate immune responses by controlling the access of leukocytes to sites of inflammatory or immune reaction in the body. We have shown that lymphocytes use a variety of different adhesion molecules or "homing receptors" to recognize organ (and/or inflammation)-specific vascular ligands or "addressins" that define the tissue position (address) of blood vessels in the body. Our studies have shown that these adhesion receptors act coordinately with G protein-linked serpentine chemoattractant receptors in a multi-step process that controls the specificity and provides combinatorial diversity in leukocyte trafficking.
A major focus of the group is on understanding the physiologic significance and control of targeted lymphocyte trafficking. To this end, we are studying the specialized homing mechanisms and functional properties of tissue infiltrating lymphocytes involved in local immune, autoimmune and regulatory responses in the GI tract (intestines, liver), skin, lungs, and other sites. Genetic, antibody and small molecule-based approaches allow us to define the role of trafficking molecules and mechanisms in models of autoimmune and infectious diseases. We are also exploring mechanisms that imprint lymphocyte homing and chemokine receptor expression during tissue-specific immune responses, and are developing techniques to recapitulate such regulation in vitro for cell targeting and therapy. Dendritic cells (DC) play an important role in this context, and we are interested in the mechanisms by which specialized DC interpret and process local environmental signals (e.g. vitamins, metabolites, cytokines) to control T cell trafficking and regulatory vs. effector activities.
In other investigations, we have identified novel lymphocyte, dendritic cell and macrophage chemoattractants and receptors, as well as monocyte and arterial wall endothelial molecules that regulate monocyte-endothelial interactions in models of atherogenesis. We are interested in the structure and function of these molecules, and their importance in disease models. Finally, we have shown that leukocytes can effectively navigate through complex chemoattractant arrays, and we are exploring the mechanisms that permit this surprising behavior through computer simulations of chemotactic behavior, and through experimental manipulation of the molecules and receptors involved.