Background: Non-suppurative destructive cholangitis (NSDS), T cell- mediated apoptotic destruction of biliary epithelial cells (BEC), occurs in autoimmune (primary biliary cirrhosis, PBC) and alloimmune (chronic graft-versus host disease, CGVHD or liver allograft rejection) diseases. The presence of NSDC in both PBC and CGVHD after engraftment of HLA- identical, MLR-negative marrow indicates that BEC-specific antigens presented by self-HLA can sensitize CTL. Our MHC-matched, MLR-negative B10.D2>BALB/c CGVHD model also causes NSDC when grafts contain CD4 T cells. Hypothesis: Class II, MHC-restricted donor CD4 T cell responses to recipient BEC antigens cause NSDC. To define the immunopathogenesis of NSDC at the cellular level, we developed methods to isolate: a) anatomic sties of NSDC from CGVHD livers; b) hepatic T cells and c) BEC from normal or CGVHD mice. We also created SV40 transformed, immortalized BEC (IBEC) lines that exhibit a BEC phenotype.
Specific Aim 1 : To define the phenotype and functions of T cells isolated from inflamed portal tracts during evolution of NSDC we will assess: a) Th1/Tc1 versus Th2/Tc2 cytokine phenotypes of CD4/CD8 T cells during evolution of NSDC by flow cytometry; b) histopathological consequences of polarizing intrahepatic inflammation to either a Th1/Tc1 or Th2/Tc2 response by antagonism of IL-12 or IL-4 using monoclonal antibodies, rIL-12 or immunization; c) effector functions and capacity of BEC- specific CD4/CD8 T cell clones to mediate NSDC in vivo after adoptive transfer; and d) Fas and perfornin/granzyme B mechanisms involved in CTL- and cytokine-mediated BEC cytotoxicity.
Specific Aim 2 : To characterize and compare fresh BEC and IBEC lines, in the presence or absence of cytokines, we will assess: a) mechanisms and regulation of apoptosis induced by anti-Fas antibodies, cell-bound FasL and TNFalpha in vitro and b) endogenous and stimulated cytokine gene and protein expression using flow cytometry, molecular techniques and ELISA. New insights into T cell- and cytokine-mediated mechanisms of NSDC immunopathogenesis are needed to develop more effective therapies for PBC and CGVHD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Prasad, Shiv A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cedars-Sinai Medical Center
Los Angeles
United States
Zip Code
Vierling, John M; Hreha, Gabriella; Wang, Haimei et al. (2011) The role of biliary epithelial cells in the immunopathogenesis of non-suppurative destructive cholangitis in murine hepatic graft-versus-host disease. Trans Am Clin Climatol Assoc 122:326-35
Xu, Junquan; Lee, Gene; Wang, Haimei et al. (2004) Limited role for CXC chemokines in the pathogenesis of alpha-naphthylisothiocyanate-induced liver injury. Am J Physiol Gastrointest Liver Physiol 287:G734-41