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.
