PMID- 26185095 OWN - NLM STAT- MEDLINE DCOM- 20160205 LR - 20181113 IS - 1527-3350 (Electronic) IS - 0270-9139 (Print) IS - 0270-9139 (Linking) VI - 62 IP - 5 DP - 2015 Nov TI - A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. PG - 1536-50 LID - 10.1002/hep.27998 [doi] AB - Autoimmune hepatitis (AIH) in humans is a severe inflammatory liver disease characterized by interface hepatitis, the presence of circulating autoantibodies, and hyper-gammaglobulinemia. There are two types of AIH, type 1 (AIH-1) and type 2 (AIH-2), characterized by distinct autoimmune serology. Patients with AIH-1 are positive for anti-smooth muscle and/or antinuclear autoantibodies, whereas patients with AIH-2 have anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 autoantibodies. Cytochrome P4502D6 is the antigenic target of anti-liver kidney microsomal type 1, and formiminotransferase cyclodeaminase is the antigenic target of anti-liver cytosol type 1. It is known that AIH, both types 1 and 2, is strongly linked to the human leukocyte antigen (HLA) alleles -DR3, -DR4, and -DR7. However, direct evidence of the association of HLA with AIH is lacking. We developed a novel mouse model of AIH using the HLA-DR3 transgenic mouse on the nonobese-diabetic background by immunization of HLA-DR3- and HLA-DR3+ nonobese-diabetic mice with a DNA plasmid, coding for human cytochrome P4502D6/formiminotransferase cyclodeaminase fusion protein. Immunization with cytochrome P4502D6/formiminotransferase cyclodeaminase leads to a sustained elevation of alanine aminotransferase, development of antinuclear autoantibodies and anti-liver kidney microsomal type 1/anti-liver cytosol type 1 autoantibodies, chronic immune cell infiltration, and parenchymal fibrosis on liver histology in HLA-DR3+ mice. Immunized mice also showed an enhanced T helper 1 immune response and paucity of the frequency of regulatory T cells in the liver. Moreover, HLA-DR3+ mice with exacerbated AIH showed reduced diversity and total load of gut bacteria. CONCLUSION: Our humanized animal model has provided a novel experimental tool to further elucidate the pathogenesis of AIH and to evaluate the efficacy and safety of immunoregulatory therapeutic interventions in vivo. CI - (c) 2015 by the American Association for the Study of Liver Diseases. FAU - Yuksel, Muhammed AU - Yuksel M AD - Section of Endocrinology, Yale University School of Medicine, New Haven, CT. AD - Laboratory of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium. AD - Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK. FAU - Wang, Yipeng AU - Wang Y AD - Section of Endocrinology, Yale University School of Medicine, New Haven, CT. AD - Clinical Research Centre for Autoimmune Liver Disease, Beijing You-an Hospital, Capital Medical University, Beijing, China. FAU - Tai, Ningwen AU - Tai N AD - Section of Endocrinology, Yale University School of Medicine, New Haven, CT. FAU - Peng, Jian AU - Peng J AD - Section of Endocrinology, Yale University School of Medicine, New Haven, CT. FAU - Guo, Junhua AU - Guo J AD - Section of Endocrinology, Yale University School of Medicine, New Haven, CT. AD - Department of Rheumatology, PLA General Hospital, Beijing, China. FAU - Beland, Kathie AU - Beland K AD - Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada. FAU - Lapierre, Pascal AU - Lapierre P AD - Immunovirology Laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada. FAU - David, Chella AU - David C AD - Department of Immunology, Mayo Clinic, Rochester, MN. FAU - Alvarez, Fernando AU - Alvarez F AD - Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada. FAU - Colle, Isabelle AU - Colle I AD - Laboratory of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium. FAU - Yan, Huiping AU - Yan H AD - Clinical Research Centre for Autoimmune Liver Disease, Beijing You-an Hospital, Capital Medical University, Beijing, China. FAU - Mieli-Vergani, Giorgina AU - Mieli-Vergani G AD - Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK. FAU - Vergani, Diego AU - Vergani D AD - Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK. FAU - Ma, Yun AU - Ma Y AD - Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK. FAU - Wen, Li AU - Wen L AD - Section of Endocrinology, Yale University School of Medicine, New Haven, CT. LA - eng GR - DK092882/DK/NIDDK NIH HHS/United States GR - R01 DK088181/DK/NIDDK NIH HHS/United States GR - P30 DK045735/DK/NIDDK NIH HHS/United States GR - DK088181/DK/NIDDK NIH HHS/United States GR - R01 DK092882/DK/NIDDK NIH HHS/United States GR - DK100500/DK/NIDDK NIH HHS/United States GR - R01 DK100500/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150825 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Autoantibodies) RN - 0 (Cytokines) RN - 0 (HLA-DR3 Antigen) RN - 0 (anti-liver kidney microsome antibody) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) SB - IM MH - Animals MH - Autoantibodies/immunology MH - Base Sequence MH - Cytochrome P-450 CYP2D6/immunology MH - Cytokines/biosynthesis MH - Disease Models, Animal MH - HLA-DR3 Antigen/immunology MH - Hepatitis, Autoimmune/*etiology MH - Humans MH - Immunization MH - Intestines/*microbiology MH - Liver/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - *Microbiota MH - Molecular Sequence Data MH - T-Lymphocytes, Regulatory/immunology PMC - PMC4763614 MID - NIHMS722531 EDAT- 2015/07/18 06:00 MHDA- 2016/02/06 06:00 PMCR- 2016/11/01 CRDT- 2015/07/18 06:00 PHST- 2015/03/13 00:00 [received] PHST- 2015/07/15 00:00 [accepted] PHST- 2015/07/18 06:00 [entrez] PHST- 2015/07/18 06:00 [pubmed] PHST- 2016/02/06 06:00 [medline] PHST- 2016/11/01 00:00 [pmc-release] AID - 10.1002/hep.27998 [doi] PST - ppublish SO - Hepatology. 2015 Nov;62(5):1536-50. doi: 10.1002/hep.27998. Epub 2015 Aug 25.