T cells are the coordinators of the immune response and are known to have an important role in the pathogenesis of Crohn's disease (CD). Because the ideal therapeutic strategy is to prevent the initiation of the immuno-inflammatory cascade it is vital to understand the molecular mechanism of T cell activation in CD. Multiple recent reports have demonstrated a critical role for the integrin family of adhesion molecules in T cell function. Of particular relevance are the 0:4 containing integrin receptors which are important in T cell adhesion, costimulation and homing. The T cell (alpha 4 containing integrins are likely to have a pivotal role in CD pathogenesis because: (1) they mediate T cell homing to the gastrointestinal tract; (2) anti-alpha4 antibodies diminish inflammation in animal models of intestinal inflammation; (3) alpha 4 beta 1 is the T cell receptor for invasin, the protein component of the outer membrane of Yersinia pseudotuberculosis which causes a subacute illness strikingly similar in several respects to CD. The goal of the project is to define the role of the beta containing integrins in the pathogenesis of CD in order to provide a rational basis for the development of novel therapies by answering the following questions: 1) Does integrin and integrin ligand expression correlate with inflammation in CD? 2) Is there altered function of T cell integrins in CD? 3) What mucosal factors are produced in CD that modulate integrin function? 4) Which integrins are involved in Yersinia pseudo tuberculosis infection?
NIH ExPorter
NIH ExPorter