Non-suppurative destructive cholangitis (NSDC), a histopathologic process originally described in primary biliary cirrhosis (PBC), recently has been noted in human chronic graft-vs-host disease (CGVHD) and in chronic rejection of human liver allografts. The occurrence of NSDC in the latter disorders indicates that alloimmune mechanisms can mediate specific hepatobiliary injury and provides circumstantial support for the hypothesis that NSDC in PBC is mediated immunologically. Since direct study of immunologic mechanisms mediating hepatobiliary injury is impossible in patients, a murine model of CGVHD has been developed in which NSDC occurs consistently.
The aims of this study are to define the evolution of NSDC in this model of CGVHD and to assess the alloimmune mechanisms involved. CGVHD is produced in irradiated Balb/c recipients by injection of B10.D2 lymphoid cells. Irradiated Balb/c mice injected with syngeneic cells serve as controls. Since these congenic strains are MHC (H-2d) and Mls (Mlsb) identical, this model closely mimics the situation in HLA,MLR-matched human bone marrow transplantation. The evolution of NSDC in this model will be studied by assessing the livers of experimental and control mice by light and electron microscopy from day 2 to 130. Histology will be graded under code using specific criteria to assess the degree of: a) portal tract and parenchymal inflammation; b) bile duct injury; and c) piecemeal necrosis. The immunohistopathologic evolution of NSDC will be studied by quantitating the proportions of B cells, monocyte/macrophages, T cells, T cell subsets, and cells of donor and recipient origin within the liver using avidin-biotin-peroxidase and immunofluorescent techniques. The proportions of cells in the injured liver will be compared to those in the spleen. The cellular requirements for the production of NSDC will be evaluated by varying the composition of the graft with respect to T helper and T suppressor cells, engrafting specific T cell subsets alloactivated in an intermediate host, and evaluating the capacity of mononuclear cells isolated from the livers of mice with CGVHD to mediate NSDC. In addition, the capacity of hepatic mononuclear cells from CGVHD mice to bind specifically to normal Balb/c livers, to proliferate when exposed to bile duct cells, and to function in in vitro assays of allohelp and allosuppression, cytotoxicity, and delayed-type hypersensitivity will be assessed. These studies should provide insight regarding the pathogenic mechanism(s) of NSDC in human CGVHD, hepatic allograft rejection, and PBC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033883-02
Application #
3232291
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1986-08-01
Project End
1989-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045