(from the application): Cell adhesion is a fundamental element of leukocyte-endothelial cell interactions and is required for extravasation of leukocytes in response to infection, for the maintenance of inflammation in many autoimmune diseases and for the recirculation of lymphocytes between blood and lymphatic tissue. The essential role of adhesion is exemplified by the severe infectious complications of patients with leukocyte adhesion deficiency. Recent studies have demonstrated that leukocyte trans-endothelial migration requires the sequential interaction of distinct receptor-ligand pairs and that de-adhesion is also required for successful transmigration. For some adhesion molecules, the mechanism of de-adhesion is well-understood, for example, L-selectin is rapidly shed from the surface upon cellular activation and the adhesive events are inherently transient. Other adhesion molecules, e.g. VCAM-1, ICAM-1 and P and E-selectin are quantitatively upregulated in response to cellular activation. In contrast, expression of the two most important leukocyte integrins that mediate endothelial adhesion, LFA-1 and VLA-4, does not change significantly. Instead, the avidity of the integrins for their ligands is increased and then decreased. The pathways that lead to integrin activation and de-activation are poorly understood. To investigate the mechanisms underlying the regulation of leukocyte integrin avidity which mediate adhesion and de-adhesion, mutant T lymphoma cell lines have been prepared that are constitutively avid for binding to ICAMs in the absence of any exogenous cellular stimulation and never de-adhere, and others have been isolated that fail to activate LFA-1 binding to ICAMs with any physiological stimulus. Preliminary studies have indicated the presence of signal transduction mutations in these cells. The goals of the proposed studies are: 1) To prepare additional mutant cell lines with distinct mutations that lead to dysregulated LFA-1; 2) To study other integrins on these cells to see if the defect in regulation is global or selective, and 3) To employ pharmacologic and molecular biologic methods to identify and characterize the mutation in each cell that resulted in dysregulated LFA-1. Understanding the mechanisms of integrin adhesion and de-adhesion may ultimately allow the selective pharmacological modulation of regulatory elements that control leukocyte trafficking, which would be a novel and exciting therapeutic approach for treating autoimmune diseases, including refractory psoriasis and rheumatoid arthritis.
| Castells, M C; Klickstein, L B; Hassani, K et al. (2001) gp49B1-alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nat Immunol 2:436-42 |
| Cherry, L K; Weber, K S; Klickstein, L B (2001) A dominant Jurkat T cell mutation that inhibits LFA-1-mediated cell adhesion is associated with increased cell growth. J Immunol 167:6171-9 |
| Tyagi, S; Klickstein, L B; Nicholson-Weller, A (2000) C5a-stimulated human neutrophils use a subset of beta2 integrins to support the adhesion-dependent phase of superoxide production. J Leukoc Biol 68:679-86 |
| Tyagi, S; Nicholson-Weller, A; Barbashov, S F et al. (2000) Intercellular adhesion molecule 1 and beta2 integrins in C1q-stimulated superoxide production by human neutrophils: an example of a general regulatory mechanism governing acute inflammation. Arthritis Rheum 43:2248-59 |
