Our primary interests are in the molecular biology of cell surface molecules governing adhesion to and transmigration through vascular endothelium. It is the vascular barrier that must be breached in the course of normal extravasation of cells into tissue compartments, and to wall off and eliminate foreign insult such as incurred by infectious agents in those tissues. This cellular traffic is responsible for desired and undesired inflammation to proceed when normal cells are involved, and it is likely that similar mechanisms operate through which neoplastic counterparts spread from one tissue to another to form cancer metastases. We have been engaged in the characterization, cloning, and functional attributes of adhesion molecules, including the lymph node homing receptor (LHR, L-selectin) in mouse and man, as well as the cartilage link family member CD44. Our molecular cloning of L-selectin revealed a novel makeup of a tandem collection of protein domains. This unique architecture defines the selectin family of adhesion receptors, and all share functions critical to interactions between circulating cells and the vasculature, and are ultimately responsible for targeting cells to sites throughout the organism.
One of our main goals is to study the role of adhesion receptors and their regulation in autoimmune and chronic inflammatory conditions. We have generated mice deficient in L-selectin expression and have elucidated the roles of this molecule in immune responses, and in the generation of hematopoietic and other organ systems. We have further placed this genetic defect in animals with various types of autoimmune syndromes to examine the effect on the outcome of these diseases. In addition, we have identified and are characterizing molecular and biological aspects of a novel adhesion pathway for extravasation of activated lymphocytes involving the cell surface molecule CD44, and have been exploring the role of this pathway during immune and autoimmune responses in animal models and directly under autoimmune settings in man. Recent approaches have included microarray and proteomic technologies. The potential role of these adhesion interactions in cancer cell dissemination and localization are also under investigation.
Our more recent efforts have focused on characterizing molecular and biological aspects of the novel adhesion pathway for lymphocyte extravasation involving the cell surface molecule CD44. These studies in both animal models and human autoimmune conditions have led us to explore the role of this adhesion pathway particularly in regulatory T cells, which are pivotal in controlling responses to infectious agents, to protecting tissues from autoimmune attacks, and for moderating responses to tumor antigens.
RESEARCH INTERESTS
Autoimmunity and inflammation
T cell activation
Regulatory T cells
Adhesion and extravasation
Leukocyte trafficking
RECENT PUBLICATIONS
Firan, M., Dhillon, S., Estess, P., Siegelman, M.H., "Suppressor potency among regulatory T cells is discriminated by functionally active CD44" Blood, 107:619-627, January 2006
Nandi, A., Estess, P. and Siegelman, M. H, "Bimolecular Complex between rolling and firm adhesion receptors required for cell arrest: CD44 association with VLA-4 in T cell extravasation" Immunity, 20:455-465 (Editorial pp. 361-362), April 2004
Siegelman, M.H., Stanescu, D., and Estess, P., "The CD44 initiated pathway of activated T cell extravasation utilizes the integrin VLA-4 but not LFA-1 for firm adhesion" J. Clin Invest., 105:683-691, 2000
Nandi, A., Estess, P., and Siegelman, M.H., "Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44" J. Biol. Chem., 275:14939-14948, 2000
Catalina M.D., Estess, P., and Siegelman, M.H., "Selective requirements for leukocyte adhesion molecules in models of acute and chronic cutaneous inflammation: participation of E- and P- but not L-selectin" Blood, 93:580-589, 1999
SIGNIFICANT PUBLICATIONS
Firan, M., Dhillon, S., Estess, P. and Siegelman, M. H., "Suppressor potency among regulatory T cells is discriminated by functionally active CD44" Blood, 107:619-627, January 2006
Estess, P., DeGrendele, H.C., Pascual, V., and Siegelman, M.H., "Functional activation of CD44 is a marker of autoimmune disease activity" J. Clin. Invest., 102:1173-1182, 1998
DeGrendele, H.C., Estess, P., and Siegelman, M.H., "Requirement for CD44 in activated T cell extravasation into an inflamed site" Science, 278:672-675, 1997
Catalina, M.D., Carroll, M.C., Arizpe, H., Takashima, A., Estess, P., Siegelman, M.H., "The route of antigen entry determines the requirement for L-selectin during immune responses" J. Exp. Med., 184:2341-2351, 1996
Siegelman, M.H., Van der Rijn, M. and Weissman, I.L., "Mouse lymph node homing receptor cDNA clone encodes a glycoprotein revealing tandem interaction domains" Science, 243:1165, 1989
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