Abstract

and/or aims) The goal of this proposal is to delineate the alterations in cell-mediated immune function which initiate and/or perpetuate IBD. The focus will be on mechanisms and significance of altered human intestinal immunoglobulin expression in IBD as assessed (1) in vitro by isolated IBD intestinal lamina propria mononuclear cells, (2) in situ in IBD intestinal tissue sections, and (3) in vivo in IBD serum. The working hypothesis is that mucosal cell- mediated immunity in general, and intestinal immunoglobulins in particular, participate in IBD by providing the central mechanism that facilitates the transition from initiating to effector events. Four basic specific aims will be pursued: (1) characterization of the immunogluobulins present in and secreted by control and IBD intestinal mononuclear cells, by evaluation of isolated cells for cytoplasmatic and cell surface immunoglobulins, examination of antigenic specificity of antibodies in IBD, studies of Fc receptor binding and cell activation and determination of restricted clonality of secreted antibodies; (2) delineation of alterations in receptors of intestinal lamina propria mononuclear cells in IBD, by examining IBD cells for functional binding to high endothelial cells in IBD, by examining IBD cell for functional binding to high endothelial venules, and fluorescent activated cell sorter (FACS) examination of IBD intestinal cells for cell surface homing receptors; (3) evaluation of the state of activation of isolated IBD intestinal mononuclear cells, by examining IBD intestinal cells for the presence of cell surface activation markers; (4) assessment of mediators of inflammation, cytokines, inhibitors of the lipoxygenase pathway and drugs used in the therapy of IBD as moculators of antibody secretion, by examining drugs used in the treatment of IBD, the effect of cytokines on IBD intestinal B cell activation and maturation, and evaluating the effects of arachidonate metabolites on antibody synthesis and secretion.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK021474-20
Application #
2684090
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hamilton, Frank A
Project Start
1978-04-01
Project End
2001-09-30
Budget Start
1998-04-01
Budget End
2001-09-30
Support Year
20
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Nishiyama, R; Sakaguchi, T; Kinugasa, T et al. (2001) Interleukin-2 receptor beta subunit-dependent and -independent regulation of intestinal epithelial tight junctions. J Biol Chem 276:35571-80
Andres, P G; Beck, P L; Mizoguchi, E et al. (2000) Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. J Immunol 164:6303-12
Muehlhoefer, A; Saubermann, L J; Gu, X et al. (2000) Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa. J Immunol 164:3368-76
Fusunyan, R D; Quinn, J J; Fujimoto, M et al. (1999) Butyrate switches the pattern of chemokine secretion by intestinal epithelial cells through histone acetylation. Mol Med 5:631-40
MacDermott, R P (1999) Chemokines in the inflammatory bowel diseases. J Clin Immunol 19:266-72
Nishimura, A; Fujimoto, M; Oguchi, S et al. (1998) Short-chain fatty acids regulate IGF-binding protein secretion by intestinal epithelial cells. Am J Physiol 275:E55-63
Moonka, D; Furth, E E; MacDermott, R P et al. (1998) Pouchitis associated with primary cytomegalovirus infection. Am J Gastroenterol 93:264-6
MacDermott, R P; Sanderson, I R; Reinecker, H C (1998) The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn's disease. Inflamm Bowel Dis 4:54-67
Fusunyan, R D; Quinn, J J; Ohno, Y et al. (1998) Butyrate enhances interleukin (IL)-8 secretion by intestinal epithelial cells in response to IL-1beta and lipopolysaccharide. Pediatr Res 43:84-90
Reinecker, H C; MacDermott, R P; Mirau, S et al. (1996) Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 111:1706-13

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