application) Primary biliary cirrhosis is a chronic autoimmune liver disease characterized by inflammatory destruction of small and medium sized intrahepatic bile ducts, leading to cholestasis, then fibrosis, cirrhosis, and its complications. Although the etiology is unknown, T cells that surround the bile ductules are the likely mediators of bile duct destruction. Other cell types within the portal infiltrate, including macrophages and B cells, probably contribute to this autoimmune process. However, the manner in which these cells communicate and collaborate to cause bile duct lesions is not understood. The hypothesis of this proposed project is that T cells orchestrate the immune attack on cholangiocytes via signaling to other cells in the liver through CD40 ligand. Specifically, expression of CD40 ligand by activated T cells in the liver stimulates B cells to increase production of immunoglobulins; activates macrophages to produce IL-12, which leads to a shift of T helper cells to the Th1 phenotype and subsequent IL-2 and IFN-gamma production; and induces cholangiocytes to undergo apoptosis at an increased rate. This hypothesis will be tested by a correlative analysis of the level of expression of CD40 ligand in the liver of PBC patients with the potential consequences of CD40-CD40 ligand interaction; such as upregulation of immunoglobulin and cytokine production, and apoptosis of cholangiocytes. Expression of CD40 and CD40 ligand will be localized in the liver with immunohistochernistry. These patient-oriented studies will be supplemented by in vitro experiments designed to study CD40-ligand induced apoptosis in cholangiocytes. These studies will provide insight into the role of T cells in the pathogenesis of PBC and provide information useful in developing new treatment modalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK002687-01A1
Application #
6128333
Study Section
Special Emphasis Panel (ZDK1-GRB-C (J4))
Program Officer
Podskalny, Judith M,
Project Start
2000-05-15
Project End
2003-03-31
Budget Start
2000-05-15
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$123,390
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mayo, Marlyn J; Mosby, James M; Jeyarajah, Rohan et al. (2006) The relationship between hepatic immunoglobulin production and CD154 expression in chronic liver diseases. Liver Int 26:187-96
Browning, Jeff; Combes, Burton; Mayo, Marlyn J (2003) Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 98:2736-41