title: Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3(+) regulatory T cells.
abstract: Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg ) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8(+) T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice to recombination-activating gene (Rag)1(-/-) recipients. We then used this robust established adoptive transfer system and co-transferred CD8(+) T cells from dnTGF-βRII mice with either C57BL/6 or dnTGF-βRII forkhead box protein 3 (FoxP3(+) ) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-βRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versus dnTGF-βRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-βRII mice. Our data reflect the therapeutic potential of wild-type CD4(+) FoxP3(+) Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: G-X
authors.initials: GX
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Ando
authors.forename: T
authors.initials: T
authors.lastname: Tomiyama
authors.forename: K
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: P
authors.initials: P
authors.lastname: Leung
authors.forename: R L
authors.initials: RL
authors.lastname: Coppel
authors.forename: A A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Z X
authors.initials: ZX
authors.lastname: Lian
authors.forename: W M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: T
authors.initials: T
authors.lastname: Joh
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D002761:Cholangitis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
keywords: autoimmunity; cholangitis; colitis; murine models; primary biliary cirrhosis