Primary biliary cirrhosis (PBC) is a biliary specific autoimmune disease characterized by lymphocytic infiltrates of portal tracts, anti-mitochondrial antibodies (AMAs) and selected destruction of the biliary epithelium. Although PBC is often considered a model autoimmune disease and there have been significant advances in defining the late stage autoimmune effectors (autoantibodies, T cells, and B/T autoepitopes) in PBC patients, such data has not been translated to new therapies. There is an extended silent preclinical phase in human PBC and, as such, the earliest events that lead to biliary damage are largely unknown. This gap between onset and clinical symptoms has frustrated efforts to understand the events that lead to breach of self-tolerance. Our laboratories will take advantage of a unique murine model of PBC, mice that express a dominant-negative TGF-? receptor II gene under control of the promoter for CD4 (dnTGF-?RII). These mice develop a robust inflammatory biliary disease and 100% penetrance of AMAs. Our progress during the current period of funding has led to important, novel and in some cases surprising results that allow us to address three critical areas that have the potential to define the immunopathology leading to breach of tolerance, cholangitis and hepatic fibrosis. First, CD8 T cells mediate biliary pathology and, more importantly, the KLRG1+ effector CD8 T cell subset accumulates in the liver, but only in the presence of defective dnTGF-?RII Tregs. Our goal will be to define the KLRG1+ phenotype, its ability to transfer disease, and the mechanism of Treg-mediated control of this critical cell subset. Second, we have shown that deletion of IL-12p35 in dnTGF-?RII mice leads not only to portal inflammation and bile duct damage, but also to fibrosis with a distinct cytokine profile. We will take advantage of this observation and serially monitor these events to define the sources of pathologic cytokines in the course of dysfunctional TGF-? signaling as well as define how IL-17 signaling is cross-regulated by cytokines in the course of a chronic immune response by taking advantage of transgenic dnTGF-?RII mice that lack IL-17A, IL-17F, IL-22, IL- 23p19 or IL-17RA in addition to unique bone marrow chimeric mouse models. Finally, our published data show that microRNA dysregulation plays a major role in autoreactive CD8 T cell mediated biliary pathology. Our existing models and novel proposed methods will allow us to correct this dysregulation and to test the effect of corrected miRNA biosynthesis on T cell activation status, and, more importantly, on immunopathology. We submit that the results of this proposal will provide insight into the mechanisms of action of CD8 effector mediated damage, will provide the opportunity to develop a biologic network of the earliest immune mediated fibrotic events and finally critical mechanistic information on the role of micro- RNA in autoimmune cholangitis. Importantly, we believe these data will potentially identify new pathways for therapeutic targeting.

Public Health Relevance

Primary biliary cirrhosis is an enigmatic immune-mediated disease of the liver which is characterized by progressive inflammation and destruction of the biliary system. Our laboratory proposes to learn more about this disease by taking advantage of a mouse model. We will study mice that recapitulate many of the features of patients with PBC and will focus on the mechanisms that lead to bile cell damage in the belief that the results will lead to better treatments for patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Huang, Wenting; Kachapati, Kritika; Adams, David et al. (2014) Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1(+) CD8 effector cells and defective T regulatory cells. J Autoimmun 50:123-34
Wang, Jinjun; Yang, Guo-Xiang; Tsuneyama, Koichi et al. (2014) Animal models of primary biliary cirrhosis. Semin Liver Dis 34:285-96
Tanaka, H; Zhang, W; Yang, G-X et al. (2014) Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3(+) regulatory T cells. Clin Exp Immunol 178:253-61
Ridgway, William M; Gershwin, M Eric (2014) Prometheus unbound: NKT cells inhibit hepatic regeneration. Hepatology 60:1133-5
Ando, Yugo; Yang, Guo-Xiang; Kenny, Thomas P et al. (2013) Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-ýý receptor type II mouse. J Autoimmun 41:111-9
Kawata, Kazuhito; Yang, Guo-Xiang; Ando, Yugo et al. (2013) Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGF*RII mice. Hepatology 58:1094-104
Tanaka, H; Yang, G-X; Iwakoshi, N et al. (2013) Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clin Exp Immunol 174:364-71
Tsuda, Masanobu; Zhang, Weici; Yang, Guo-Xiang et al. (2013) Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFýý receptor type II mice. Hepatology 57:806-16
Ando, Yugo; Yang, Guo-Xiang; Tsuda, Masanobu et al. (2012) The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice. Hepatology 56:1418-26