title: Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy.
abstract: There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor β receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4(-/-)Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-γ produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4(-/-)Tg mice with established disease at 8-9 weeks of age with C57BL/6 control mice. Such parabiotic "twins" had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4(-/-)Tg and CD8(-/-) mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8(+) T effector cells in the presence of wild type CD4 cells was noted. In conclusion, "correcting" the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis.
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: yjingb@mail.ustc.edu.cn.
authors.forename: Jing-Bo
authors.initials: JB
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: wangyh8@mail.ustc.edu.cn.
authors.forename: Yin-Hu
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: ywei0702@mail.ustc.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: fangting@mail.ustc.edu.cn.
authors.forename: Fang-Ting
authors.initials: FT
authors.lastname: Lu
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: mahongdi@ustc.edu.cn.
authors.forename: Hong-Di
authors.initials: HD
authors.lastname: Ma
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: zzbin@mail.ustc.edu.cn.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Zhao
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: jyanjie@mail.ustc.edu.cn.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Jia
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: wayne012@mail.ustc.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan. Electronic address: tsuneyama.koichi@tokushima-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, OH 45220, USA. Electronic address: ridgwawm@uc.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA. Electronic address: megershwin@ucdavis.edu.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China. Electronic address: zxlian1@ustc.edu.cn.
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000601:surgery*; D001652:Bile Ducts / Q000276:immunology / Q000473:pathology; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002761:Cholangitis / Q000276:immunology / Q000601:surgery*; D004195:Disease Models, Animal; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology / Q000601:surgery*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010227:Parabiosis / Q000379:methods*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Bone marrow chimeric mice; CD4(+) T cells; Cholangitis; Parabiosis; Primary biliary cirrhosis; Regulatory T cells