Proper interactions of two Ig family molecules, CD28 and CTLA-4, with their receptors, B7-1 and B7-2, are critical elements required for self-tolerance, co-stimulation, and normal immune responses. We have manipulated By-mediated costimulation in mice, thereby generating two new models for colitis induction. Transgenic mice that constitutively express a soluble B7-2 Ig Fc fusion protein spontaneously develop inflammation with some features in common with ulcerative colitis. It has been previously shown that transfer of CD4+ CD45RBhigh T cells to RAG 1-/- mice leads to a colitis mediated by Th1 cytokines that has some features in common with Crohn's disease. We have recently found that injection of a soluble B7-2 Ig Fc fusion protein accelerates pathogenesis and increases its severity following T cell transfer, apparently without altering the Crohn's disease-like features of this inflammation. In order to understand how altering the quality and quantity of B7-mediated costimulation can lead to intestinal inflammation, we intend to use in vitro and in vivo methods to characterize the cell types and cytokines responsible for pathogenesis in these two models. Additionally, we will carry out experiments to define the molecular basis for pathogenesis mediated by soluble B7-2 molecules. Humans produce soluble B7 molecules that can be detected in serum, and CTLA-4 polymorphisms are associated with autoimmune disease susceptibility. Therefore the results from these studies should provide new insights into the in vivo biology of costimulation and they should increase our understanding as to how altering costimulatory activity may influence the severity of IBD.
Showing the most recent 10 out of 277 publications
