A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation

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. and Wen, L. 2015. A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology. 62 (5), pp. 1536-1550. https://doi.org/10.1002/hep.27998

TitleA novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation
TypeJournal article
AuthorsYuksel, 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. and Wen, L.
Abstract

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.

JournalHepatology
Journal citation62 (5), pp. 1536-1550
ISSN1527-3350
Year2015
PublisherAmerican Association for the Study of Liver Diseases
Wolters Kluwer
Digital Object Identifier (DOI)https://doi.org/10.1002/hep.27998
Publication dates
Published20 Oct 2015

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