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10.1002/hep.27998

http://scihub22266oqcxt.onion/10.1002/hep.27998
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suck abstract from ncbi


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pmid26185095      Hepatology 2015 ; 62 (5): 1536-50
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  • A novel ?humanized mouse? model for autoimmune hepatitis and the association of gut microbiota with liver inflammation #MMPMID26185095
  • Yuksel M; Wang Y; Tai N; Peng J; Guo J; Beland K; Lapierre P; David C; Alvarez F; Colle I; Yan H; Mieli-Vergani G; Vergani D; Ma Y; Wen L
  • Hepatology 2015[Nov]; 62 (5): 1536-50 PMID26185095show ga
  • Background: 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 anti-nuclear (SMA/ANA) autoantibodies whereas patients with AIH-2 have anti-liver kidney microsomal type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. Cytochrome P4502D6 (CYP2D6) is the antigenic target of anti-LKM1 and formiminotransferase cyclodeaminase (FTCD) is the antigenic target of anti-LC1. It is known that AIH, both type-1 and type-2, is strongly linked to the Human Leukocyte Antigen (HLA) alleles -DR3, -DR4 and -DR7. However, the direct evidence of the association of HLA with AIH is lacking. Methods: We developed a novel mouse model of AIH using the HLA-DR3 transgenic mouse on the non-obese diabetic (NOD) background (HLA-DR3 NOD) by immunization of HLA-DR3? and HLA-DR3+ NOD mice with a DNA plasmid, coding for human CYP2D6/FTCD fusion protein. Results: Immunization with CYP2D6/FTCD leads to a sustained elevation of alanine aminotransferase (ALT), development of ANA and anti-LKM1/anti-LC1 autoantibodies, chronic immune cell infiltration and parenchymal fibrosis on liver histology in HLA-DR3+ mice. Immunized mice also showed an enhanced Th1 immune response and paucity of the frequency of regulatory T-cell (Treg) 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.
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