Animal Models of Autoimmune Liver Diseases: a Comprehensive Review

Liu, Shou Pei; Bian, Zhen; Zhao, Zhi Bin; Wang, Jinjun; Zhang, Weici; Leung, Patrick S.C.; Li, Liang; Lian, Zhe Xiong

doi:10.1007/s12016-020-08778-6

Cited by 24 publications

(17 citation statements)

References 180 publications

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“…In this study, we have proved the effect of Gal-9 in enhancing the therapeutic effect of ERCs in a mouse model of ConA-induced AIH. Our results are encouraging, but the in-depth mechanism studies are warranted in different hepatitis models [ 42 ].…”

Section: Discussionmentioning

confidence: 86%

Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis

et al. 2021

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Background Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. Methods ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. Results After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. Conclusions The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.

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Section: Discussionmentioning

confidence: 86%

Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis

et al. 2021

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“…The remaining mice were randomly divided into control-c group ( n = 6), CYP2D6 (CYP) group ( n = 8), CYP2D6+celastrol (CYP + Cel) group ( n = 8), celastrol-chronic (Cel-c) group ( n = 6). For mice in the CYP and CYP + Cel groups, multiple high-pressure tail vein injections of plasmid were used to develop AIH mouse models as reported in previous literature ( Wang et al, 2019 ; Liu S.-P. et al, 2020 ; Wang H. et al, 2020 ). Twenty-one days after the adenovirus injection, the CYP + Cel and Cel group mice were orally administered with celastrol (3 mg/kg) once a day for 14 days.…”

Section: Methodsmentioning

confidence: 99%

“…Since it can easily be recognized by liver-kidney microsomal antibodies 1 (LKM-1), cytochrome P4502D6 (CYP2D6) is a major autoantigen in type 2 AIH ( Heneghan et al, 2013 ; Webb et al, 2018 ). Liver-specific overexpression of human gene coding CYP2D6 in mice can induce chronic progress of autoimmune liver damage, in turn leading to autoantibody generation ( Liu S.-P. et al, 2020 ; Wang H. et al, 2020 ). Therefore, the present study examined the biological effects of celastrol in both acute and chronic experimental models of AIH.…”

Section: Introductionmentioning

confidence: 99%

Celastrol Alleviates Autoimmune Hepatitis Through the PI3K/AKT Signaling Pathway Based on Network Pharmacology and Experiments

Wang

Huang

et al. 2022

Front. Pharmacol.

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Objective: This work aims to explore the potential targets and underlying therapeutic mechanisms of celastrol in autoimmune hepatitis (AIH) through network pharmacology and experiments on Laboratory Animals.Methods: A drug-target interaction network was constructed to predict the possible targets of celastrol and their potential relationship with the drug; docking studies were also performed for validation. This study used both acute and chronic rodent models of autoimmune hepatitis. Gross appearance of liver and spleen were obtained from murine models, hematoxylin-eosin staining and Sirius red staining were performed to examine hepatic inflammation and fibrosis respectively. By combining molecular docking and enrichment analysis results, the most prominent signaling pathway was selected and further confirmed by Western blot in AIH models administered with celastrol.Results: In total, 82 common targets of celastrol and AIH were obtained from databases, identified by network pharmacology, and adequately enriched. Among them, PIK3R1, SRC, MAPK1, AKT1, and HRAS were selected as the top 5 closely related targets to celastrol. They all performed effectively in molecular docking, with AKT1 and PIK3R1 exhibiting more-prominent binding energy. Subsequently, celastrol administration significantly ameliorated hepatitis and liver fibrosis by reducing AKT1 and PI3K phosphorylation in both acute liver injury and chronic models of autoimmune hepatitis.Conclusion: In summary, celastrol significantly attenuates autoimmune hepatitis by suppressing the PI3K/AKT signaling pathway, confirmed by validated animal models. These findings may help identify the mechanism involved in the anti-inflammatory action of celastrol in autoimmune hepatitis and provide ideas for future comprehensive studies.

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“…Con A-induced hepatitis is a useful model for highly specific activation of T cells and used widely in research for investigating the role of T cells in AIH, but it is acute hepatic injury model not chronic, also it is a cytokine-dependent and antigen-independent. The use of liver homogenate for inducing hepatitis is a simple approach and has been widely used in the search for the mechanisms of AIH, but these models are induced by transferring of liver extracts to the animal body with a mostly unidentified composition [ 92 ]. There is therefore a need for better EAH models.…”

Section: Future Perspectivesmentioning

confidence: 99%

Stem cell therapies for autoimmune hepatitis

et al. 2021

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Autoimmune hepatitis is a chronic inflammatory hepatic disorder which may cause liver fibrosis. Appropriate treatment of autoimmune hepatitis is therefore important. Adult stem cells have been investigated as therapies for a variety of disorders in latest years. Hematopoietic stem cells (HSCs) were the first known adult stem cells (ASCs) and can give rise to all of the cell types in the blood and immune system. Originally, HSC transplantation was served as a therapy for hematological malignancies, but more recently researchers have found the treatment to have positive effects in autoimmune diseases such as multiple sclerosis. Mesenchymal stem cells (MSCs) are ASCs which can be extracted from different tissues, such as bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs interact with several immune response pathways either by direct cell-to-cell interactions or by the secretion of soluble factors. These characteristics make MSCs potentially valuable as a therapy for autoimmune diseases. Both ASC and ASC-derived exosomes have been investigated as a therapy for autoimmune hepatitis. This review aims to summarize studies focused on the effects of ASCs and their products on autoimmune hepatitis.

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Animal Models of Autoimmune Liver Diseases: a Comprehensive Review

Cited by 24 publications

References 180 publications

Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis

Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis

Celastrol Alleviates Autoimmune Hepatitis Through the PI3K/AKT Signaling Pathway Based on Network Pharmacology and Experiments

Stem cell therapies for autoimmune hepatitis

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