Scientific Abstract

Proposal No.  IBD-0137R
Principal Investigator:  Ellen C. Ebert, M.D.
Applicant Organization:  University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School (New Brunswick, U.S.A.)
Project Title:  The role of human tropomyosin 5 in the destruction of intestinal epithelial cells in ulcerative colitis: clinical implications
Period of Award:  March 1, 2005 – August 31, 2007

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that may be perpetuated by autoimmune processes.  Although a variety of antibodies against epithelial cells (ECs) and bacteria have been found in the serum of patients with UC, it is unclear whether these are epiphenomena or related to the disease process.  The hypothesis of this study is that antibodies directed against human tropomyosin isoform 5 (hTM5) mediate damage and death of colonic ECs in UC.  We have found IgG recognizing hTM5 in the serum and colon of patients with UC, but not Crohn's disease (CD).  This autoantibody is cytotoxic toward normal colonic, but not small bowel epithelial cells. hTM5, the predominant isoform of this class of cytoskeletal proteins found in the colon epithelium, is an intracellular protein but is transported to the surface of colon, but not small bowel, epithelial cells.  Serum IgG against hTM5 may bind to this surface protein and kill the epithelial cells suggesting that disease pathogenesis originates with the serum rather than the mucosa.
 
This project will determine whether this finding can be utilized in novel diagnostic and therapeutic modalities.  First, the specificity of this cytotoxic factor against hTM5 (CF-TM5) for UC will be confirmed by testing the ability serum from patients with UC, CD, and non-IBD colitis to lyse a normal epithelial cell line (NCM460). The results will be correlated with disease activity, extent of disease, subsequent course, and immunosuppressive medications.  While we know that CF-TM5 injures normal colonic epithelium, we will also determine whether it similarly injures epithelium from patients with UC.  Next, patients with indeterminate colitis will be tested for CF-TM5 and for hTM5 Abs in the serum to assess whether these tests help to identify those that ultimately show the characteristics of UC.  Finally, monoclonal Abs that block CF-TM5 will be developed with the aim of eventually administering them by enema to patients with active left-sided UC.