Primary biliary cirrhosis (PBC) is a liver specific autoimmune disease characterized by portal tract lymphocytic infiltration, selective destruction of biliary epithelial cells and antimitochondrial antibodies (AMAs). Our lab has been instrumental in advancing the study of PBC, work which began nearly 25 years ago with the identification and cloning of the mitochondrial autoantigens. However, a breakthrough in PBC requires an animal model and over the past several years our laboratory has described several such models. However, the model which recapitulates in greater similarity the features of human PBC, is a mouse transgenic for directed expression of a dominant negative form of TGF2 receptor type II (dnTGF2-RII) under the direction of the CD4 promoter. Using funds from an R21 award that led to the development of this model, we have reported that dnTGF2-RII mice develop AMAs of the identical specificity as humans, similar cytokine profiles in both sera and liver and have liver histology and immunohistochemistry similar to humans with PBC. Further, adoptive transfer of splenic dnTGF2-RII CD8+ T cells into B6 Rag1-/- mice transfers autoimmune cholangitis, whereas similar transfer of dnTGF-2RII CD4+ T cells transfers colitis. We propose to take advantage of these and other data, a logical extension of our R21 award to extensively dissect the immunopathogenic mechanisms that lead to biliary autoimmune disease. In particular, we propose three critical aims. Firstly, we have demonstrated that dnTGF2-RII CD8+ T cells are sufficient to transfer biliary pathology to Rag1-/- recipients and we propose to define the mechanism of dnTGF2-RII CD8+ T cell mediated disease using transfer and mixed bone marrow chimeric studies and an ontogenetic analysis of CD8+ T cells and an analysis of CD8+ T cell cytokine expression. Secondly, we will define whether dnTGF2-RII CD8+ T cell autoimmunity is antigen specific by taking advantage of our expertise in class I tetramer technology and by using dnTGF2-RII mice with a restricted TCR repertoire. Finally, we have recently published that deleting IL-12p40, but not IFN-3, in dnTGF2- RII mice prevents the development of disease. This is exciting in light of recent IL-12 polymorphism demonstrated in genome-wide association studies of human PBC. We will take advantage of our ability to produce unique murine constructs and we will dissect the cytokine mediated pathways that produce disease. We will backcross p35-/- mice (lack IL-12), p19-/- mice (lack IL-23), p35/19-/- mice (lack IL-12 and IL-23), p35/40- /- mice (lack IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A-/- mice (lack IL-12 and IL-17A) mice to dnTGF-2RII mice. Furthermore, as sera IL-22 is significantly elevated in dnTGF-2RII mice, we will also backcross IL-22-/- mice onto dnTGF-2RII mice to further define the protective or inflammatory role of IL-22. We submit that use of our unique murine constructs and our rigorous dissection of the mechanism of autoimmune cholangitis in this model will provide important clues towards successful modulation of human PBC.

Public Health Relevance

Primary biliary cirrhosis is a cryptic autoimmune disease of humans characterized by autoantibodies and inflammation of the biliary system of the liver. Progress in this disease has been hampered by the absence of an animal model. Our lab proposes to take advantage of a model that recapitulates many of the features of human PBC and study the mechanisms of disease with the belief that such data will lead to a breakthrough in human PBC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090019-02
Application #
8152134
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2010-09-30
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$433,422
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zhang, Weici; Zhang, Ren; Zhang, Jun et al. (2018) Proteomic analysis reveals distinctive protein profiles involved in CD8+ T cell-mediated murine autoimmune cholangitis. Cell Mol Immunol 15:756-767
Bae, Heekyong R; Hodge, Deborah L; Yang, Guo-Xiang et al. (2018) The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. Hepatology 67:1408-1419
Ma, Hong-Di; Zhao, Zhi-Bin; Ma, Wen-Tao et al. (2018) Gut microbiota translocation promotes autoimmune cholangitis. J Autoimmun 95:47-57
Ma, Hong-Di; Ma, Wen-Tao; Liu, Qing-Zhi et al. (2017) Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8+ T cell activation. J Autoimmun 78:19-28
Yang, Jing-Bo; Wang, Yin-Hu; Yang, Wei et al. (2016) Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy. J Autoimmun 66:108-17
Tian, Jijing; Yang, Guoxiang; Chen, Huan-Yuan et al. (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202-4213
Wang, Jinjun; Yang, Guoxiang; Dubrovsky, Alana Mari et al. (2016) Xenobiotics and loss of tolerance in primary biliary cholangitis. World J Gastroenterol 22:338-48
Yang, G-X; Sun, Y; Tsuneyama, K et al. (2016) Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice. Clin Exp Immunol 185:154-64
Bae, Heekyong R; Leung, Patrick S C; Tsuneyama, Koichi et al. (2016) Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology 64:1189-201
Hsueh, Yu-Hsin; Chang, Yun-Ning; Loh, Chia-En et al. (2016) AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis. J Autoimmun 66:89-97

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