Liver injury in primary biliary cirrhosis is characterized by T cell-mediated destruction of interlobular and septal bile ducts. An understanding of specific mechanisms by which T cells mediate bile duct destruction could form a rational basis for new treatments of this disorder. Elucidation of the responsible mechanisms requires a systemic study of the functions of T cells isolated from the liver during the evolution of bile duct destruction. Murine graft-versus-host disease results in bile duct destruction that is histologically similar to that in primary biliary cirrhosis. The long-term objective of this project is to define the T cell mechanisms mediate bile duct destruction in murine graft-versus-host disease.
The specific aims are: 1) to determine the capacity of BlO.D2 (graft) spleen total T, CD4 T, and CD8 T cells to mediate NSDC in vivo in BALB/c (host) mice. The capacity of purified graft total T, CD4 T, and CD8 T lymphocytes to mediate bile duct destruction after transfer into host mice will be determined. The in vitro functions of T cells isolated from the liver during murine graft-versus-host disease will be determined. 2) to determine the abilities of liver T helper 1 and T helper 2 T cells to induce bile duct destruction in murine graft versus-host disease. Liver T helper 1 or 2 cells will be increased during graft-versus-host disease by treatment with antibody to interleukin 4 or corticosterone. The effects of increasing T helper 1 or 2 cells on the histological grade and kinetics of bile duct destruction will be measured. 3) to define the liver T cell clones that mediate bile duct destruction during graft-versus-host disease. T cell will be cloned and characterized. The capacity of T cell clones to mediate bile duct destruction will be determined. 4) to define the factors that regulate the preferential hepatic homing (migration) of graft-versus-host disease. The capacity of BlO.D2 (donor) total T, CD4, and CD8 to home to portal tracts of the BALB/c (host) mice will be determined by means of autoradiography. The role of lymphocyte adhesion molecules in regulating homing to the liver will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI033060-04
Application #
2068027
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1992-07-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201