The overall hypothesis for this proposal is that in patients with ulcerative colitis (UC) the colonic epithelium expresses autoantigen(s) which ma drive the immune destruction of the epithelial cells. We earlier identified a putative colonic autoantigen, p40, that belongs to cytoskeletal tropomyosin (TM) family, and majority of UC sera react with p40/TM. Utilizing recombinant hTM isoforms (hTM-5) and isoform specific monoclinal antibodies (mAb) developed by us, we have observed that the normal colon epithelial cells (CEC) contain mostly hTM5 and hTM4 and not hTM1-3. We demonstrated autoantibody response in UC against hTM5 and hTM1. We will examine if there is any qualitative and/or quantitative differences in hTM isoform expression I CEC from UC compared. Using the hTM5 isoform, we identified two HLA DR2-binding peptides. We will focus on T cell responses against hTM5 and the peptides. We will also examine I cells responses against hTM4 and other hTM isoforms. For T cell responses, we will use both peripheral blood mononuclear cells (PBMC) and lamina propria lymphocytes (LPL). We have shown both in UC mucosa as well as in selected colon cancer cells that UC associated autoantibodies bind at the same site as the 7E12H12 mAb (developed by us earlier using highly enriched p40) does. This mAb has unique organ distribution such as colon, biliary tract, skin, eyes and joints. Recently we identified that 7E12H12 mAb reacts with unioval colonic epithelial protein (CEP) of Mr>200K. Preliminary experiments suggest that CEP may act as a """"""""shuttle"""""""" to externus hTM5. We will critically examine the relationship between hTMs and CEP. Using purified CEP, we will also be cloned. Human colon cDNA expression libraries from normal and UC colon mucosa and cDNA libraries from two colon cancer cell lines are developed and will be utilized.

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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Hamilton, Frank A
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University of Medicine & Dentistry of NJ
Internal Medicine/Medicine
Schools of Medicine
United States
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Das, Koushik K; Xiao, Hong; Geng, Xin et al. (2014) mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN). Gut 63:1626-34
Ebert, Ellen C; Geng, Xin; Bajpai, Manisha et al. (2009) Antibody to tropomyosin isoform 5 and complement induce the lysis of colonocytes in ulcerative colitis. Am J Gastroenterol 104:2996-3003
Mirza, Zafar K; Sastri, Bhagyalakshmi; Lin, Jim J-C et al. (2006) Autoimmunity against human tropomyosin isoforms in ulcerative colitis: localization of specific human tropomyosin isoforms in the intestine and extraintestinal organs. Inflamm Bowel Dis 12:1036-43
Glazier, Kenneth D; Palance, Adam L; Griffel, Louis H et al. (2005) The ten-year single-center experience with 6-mercaptopurine in the treatment of inflammatory bowel disease. J Clin Gastroenterol 39:21-6
Biancone, Livia; Palmieri, Giampiero; Lombardi, Antonella et al. (2003) Tropomyosin expression in the ileal pouch: a relationship with the development of pouchitis in ulcerative colitis. Am J Gastroenterol 98:2719-26
Mirza, Z K; Das, K K; Slate, J et al. (2003) Gastric intestinal metaplasia as detected by a monoclonal antibody is highly associated with gastric adenocarcinoma. Gut 52:807-12
Zimmerman, Robert L; Das, Kiron M; Fogt, Franz et al. (2002) The Das-1 immunostain is useful for discriminating metastatic colon adenocarcinoma from cholangiocarcinoma and hepatocellular carcinoma. Oncol Rep 9:1369-72
Lin, Jenny L-C; Geng, Xin; Bhattacharya, Sangeeta Das et al. (2002) Isolation and sequencing of a novel tropomyosin isoform preferentially associated with colon cancer. Gastroenterology 123:152-62
Rogge-Wolf, Claudia; Seldenrijk, Cornelis A; Das, Kiron M et al. (2002) Prevalence of mabDAS-1 positivity in biopsy specimens from the esophagogastric junction. Am J Gastroenterol 97:2979-85
Dasgupta, A; Kesari, K V; Ramaswamy, K K et al. (2001) Oral administration of unmodified colonic but not small intestinal antigens protects rats from hapten-induced colitis. Clin Exp Immunol 125:41-7

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