Although extensive work has been done in the area of leukocyte trafficking in normal and inflamed tissues such as the skin and small intestine, the colon is relatively unexplored. We hypothesize that selective combinations of adhesion molecule expression identifies subsets of T cells that preferentially home to the colon. This hypothesis is supported by findings that subsets of lymphocytes, via their expression of unique combination of adhesion molecules, manifest differential tissue localization. Furthermore, we postulate that altered adhesion molecule expression, in part, explains the massive influx of T cells seen during colonic inflammation. Based on these hypotheses, the specific aims of my proposal are:
Aim 1. Characterize the inflammation in a chronic spontaneous mouse colitis model, the keratin-8 deficient (K8 -/-) mice. In this aim we will characterize the immune response associated with the K8 -/- colitis. Although K8 is a major keratin in the small and large intestine, the colon is the primary target of inflammation in K8 -/- mice. We find that K8 -/- colitis is associated with Th2 cytokine production which is amenable to antibiotic treatment.
Aim 2. Compare adhesion and trafficking molecule expression in T and endothelial cells within lamina propria of the colon and small intestine, under normal and inflammatory conditions, using K8 +/+ and K8 -/- mice. Here we will use flow cytometry and immunohistochemistry to determine differential adhesion and trafficking molecule expression by colon endothelial and T cells as compared with other tissues, including the small intestine.
Aim 3. Determine whether molecules identified in aim 2 mediate recruitment of colon lamina propria lymphocytes in vivo in normal and inflamed colons. Here we will study the role of various adhesion molecules, by perfoming adoptive cell transfers and using blocking antibodies in short-term homing assays. The K8 -/- mouse is a unique model of inflammatory bowel disease (IBD) in that it represents a primary epithelial cell defect, and provides significant cell number to study inflammation and homing to the colon. The proposed study should improve our understanding of immune cell trafficking to the colon, offer insights into possible IBD pathogenic mechanisms, and potentially unfold new therapeutic targets to consider for IBD.
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