Inflammatory bowel disease (IBD) is characterized by extensive inflammation and immune destruction of the intestine without an obvious inciting agent. There is evidence that, a major pathogenic component in IBD is poorly regulated activation of several immune effector mechanisms. We have studied human intestinal mononuclear cells from normal individuals and patients with IBD. We have found differences in isotype and subclass usage, differences in cytokine expression and differences in Ig gene usage. It has been difficult to ascribe primary and secondary events to these changes. We have therefore established an isograft model of intestinal immunity in which fetal or neonatal intestine is placed subcutaneously in normal or immune deficient mice. These isografts develop into morphologically normal intestine. We have characterized their immune development and recirculation of lymphocytes to these isografted intestines and shown that they recapitulate normal ontogeny. In addition we have preliminary data suggesting tumor necrosis factor (TNF) has an important role in mucosal development and that this role can be experimentally examined in an isograft model. Mice mutant for T cell receptor TCR provide a model of intestinal inflammation. Preliminary data suggest that the isograft can be used to study the genesis of disease in these mutant mice. The overall aim of this proposal is to define the role of TNF in the establishment and maintenance of the gut mucosal immune system and to study a model for inflammatory bowel disease (T cell receptor mutant mice) which is amenable to therapeutic modulation. Techniques used will include cell separation, immuno- histochemistry, in situ hybridization, RNA and PCR analyses and DNA sequencing. These studies will define the mechanisms that establish and maintain cellular and regional differentiation of the normal gut immune system and may provide insights about the pathways leading to its dysregulation in inflammatory bowel diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK050976-05
Application #
6093319
Study Section
Special Emphasis Panel (SRC (05))
Program Officer
Hamilton, Frank A
Project Start
1995-09-30
Project End
2001-08-31
Budget Start
1999-03-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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