title: Immunological potential of cytotoxic T lymphocyte antigen 4 immunoglobulin in murine autoimmune cholangitis.
abstract: Cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig) is an important regulator of T cell activation and a fusion protein directed at CD80 and CD86; it blocks co-stimulatory signalling and T cell activation. We have taken advantage of a murine model of human primary biliary cirrhosis (PBC), mice expressing a transforming growth factor (TGF)-β receptor II dominant negative (dnTGF-βRII) transgene to address the potential therapeutic efficacy of CTLA-4 Ig. To mimic patients with PBC at different stages or duration of disease, we treated mice with either CTLA-4 Ig or control IgG three times weekly from 3 to 12 or 24 weeks of age, or from 12 to 24 weeks of age. CTLA-4 Ig treatment from 3 weeks of age significantly reduced liver inflammation to 12 weeks of age. Treatment initiated at 12 weeks of age also ameliorated the autoimmune cholangitis at 24 weeks of age. However, in mice treated at 3 weeks of age, suppression of liver inflammation was not sustained and colitis was aggravated when treatment was extended to 24 weeks of age. Our data indicate that, in dnTGF-βRII mice, CTLA-4 Ig treatment has short-term beneficial effects on autoimmune cholangitis, but the effect varies according to duration of treatment and the time in which therapy was initiated. Further dissection of the events that lead to the reduction in therapeutic effectiveness of CTLA-4 Ig will be critical to determining whether such efforts can be applied to human 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.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
authors.forename: G-X
authors.initials: GX
authors.lastname: Yang
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.|Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tomiyama
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.|Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
authors.forename: P S C
authors.initials: PS
authors.lastname: Leung
authors.affiliation: Department of Microbiology, Monash University, Melbourne, Victoria, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Coppel
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Joh
authors.affiliation: Department of Immunology, Bristol Myers Squibb, Princeton, NJ, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Nadler
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Ansari
authors.affiliation: Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Sacramento, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bowlus
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity / Q000187:drug effects; D060908:CTLA-4 Antigen / Q000276:immunology*; D002761:Cholangitis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000276:immunology; D007136:Immunoglobulins / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D060908:CTLA-4 Antigen; D007074:Immunoglobulin G; D007136:Immunoglobulins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: autoimmunity; cholangitis; colitis; murine models; primary biliary cirrhosis