Inflammatory bowel disease (IBD) is a group of chronic, relapsing and remitting inflammatory conditions that affect individuals throughout the life. Although the status of IBD as a canonical autoimmune disease has risen steadily by accumulated studies, it is not known whether the intestinal epithelial cell-derived proteins are involved in the pathogenesis of IBD. Recently, we have identified a mammalian lectin, galectin-4, as a colonic epithelial cell-derived pathogenic mediator in the exacerbation of colitis by using serological analysis of recombinant cDNA expression libraries (SEREX) in which cDNA libraries generated from colonic epithelial cells from T cell receptor alpha knockout (TCRalpha KO) mice were screened by using purified immunoglobulins from the TCRalpha KO mice. This discovery provides us a great opportunity to more closely examine the role of self-lectin originating from colonic epithelial cells in the pathogenesis of colitis. Based on our preliminary studies, we hypothesize that the colonic epithelial cell-derived galectin-4 contributes to the exacerbation of colitis by cross-linking the specific glycoreceptors and stimulating interleukin (IL)-6 production by the pathogenic T cells. In this application, we will initially plan to define our hypothesis by administration of recombinant galectin-4 into chronic colitis prone mice. We also plan to examine the therapeutic beneficial of in rive neutralization of galectin-4 activity on the chronic colitis by administration of galectin-4-specific monoclonal antibodies. In addition, the characteristic of galectin- 4/pathogenic T cell interaction and the involvement of immunological synapse and alpha2,3-sialyltransferase-I in galectin-4-induced IL-6 expression will be examined. These studies will not only enhance understanding of the pathogenic mechanisms of IBD but also provide important information to develop new therapeutic approaches for human IBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Carrington, Jill L
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Massachusetts General Hospital
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