Future Perspective: Immunomodulatory Therapy for Autoimmune Hepatitis

Sebode, Marcial; Lohse, Ansgar W.

doi:10.1159/000360493

Cited by 4 publications

(5 citation statements)

References 46 publications

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“…There are controversies in scientific research regarding the number of Treg present in AHI. Though the modulating function of the cell appears to be compromised [80,81]. However, in treated patients with IL-2, the Treg number is higher than untreated patients.…”

Section: Autoimmune Hepatitis and Systemic Lupus Erythematosusmentioning

confidence: 99%

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

Reichert¹,

Cunha²,

Levy³

et al. 2017

Lymphocyte Updates - Cancer, Autoimmunity and Infection

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Treg cells CD4+CD25+FOXP3+ have a specific function in the tolerance of autoantigens and regulation of the immune response. Modulation of differentiation pathways and the use of Treg cells in cell therapy have been reported in autoimmune diseases, systemic lupus erythromatosis, autoimmune hepatitis, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, graft-versus-host disease, bone marrow transplantation and solid organs. The expansion of Treg cells in vivo occurs through low-dose IL-2 treatment. However, because of the heterogeneity and variability of Treg cells, the isolation of peripheral blood cells, through the technique of leucopheresis by GMP (good manuring practice), for in vitro expansion is difficult, necessitating a large combination of specific and reliable cellular markers. Currently, two specific markers, Helios and neuropilin-1, are being studied to facilitate the differentiation of thymus Treg cells and peripheral Treg cells. However, Treg cells induced in vitro are unstable. Modulation of the FOXP3 gene in the CNS1 and CNS2 region is an alternative to maintaining the stability of expanded Treg cells in vitro.

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Section: Autoimmune Hepatitis and Systemic Lupus Erythematosusmentioning

confidence: 99%

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

Reichert¹,

Cunha²,

Levy³

et al. 2017

Lymphocyte Updates - Cancer, Autoimmunity and Infection

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“…However, recent reports found no impairment in the numbers of Tregs in the peripheral blood of AIH patients. Instead, the intrahepatic frequency of these cells was higher and correlated with the degree of the inflammation in the liver of these patients [ 82 , 83 , 101 ]. It was argued that the discrepancies may be due to immunotherapy-induced reductions in Treg numbers and changes in Treg phenotypic markers as a result of disease activity and/or treatment [ 101 , 102 ].…”

Section: Role Of Tregs In Aih Development In Traf6∆tec Micementioning

confidence: 99%

“…Instead, the intrahepatic frequency of these cells was higher and correlated with the degree of the inflammation in the liver of these patients [ 82 , 83 , 101 ]. It was argued that the discrepancies may be due to immunotherapy-induced reductions in Treg numbers and changes in Treg phenotypic markers as a result of disease activity and/or treatment [ 101 , 102 ]. The increased intrahepatic frequency of Tregs in AIH patients reported by Peiseler et al [ 82 ] and Taubert et al [ 83 ] is in agreement with our data showing increased numbers of Tregs in the liver of Traf6∆TEC mice.…”

Section: Role Of Tregs In Aih Development In Traf6∆tec Micementioning

confidence: 99%

“…LSECs express high levels of MHCII and costimulatory molecules and can capture and process soluble antigen to activate CD4 + T-cells [ 104 , 105 ]. Priming of CD4 + T-cells by LSECs results in Foxp3 expression and differentiation of CD4 + T-cells into Tregs, leading to the suppression of AIH [ 36 , 101 , 106 , 107 ]. Whether these cells also regulate the production of Foxp3 + T-cells in the liver of Traf6∆TEC mice awaits further experimentation.…”

Section: Role Of Tregs In Aih Development In Traf6∆tec Micementioning

confidence: 99%

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Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

Alexandropoulos

Bonito

Weinstein

et al. 2015

IJMS

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Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.

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“…The immunological mechanism of AIH remains to be elucidated. A lack of response to treatment may lead to end-stage liver disease ( 4 – 6 ).…”

Section: Introductionmentioning

confidence: 99%

Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis

Fan¹,

Wang²,

Xiao³

et al. 2015

Molecular Medicine Reports

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Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T-cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. A mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA-induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin-eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis-associated genes and proteins were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA-induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon-γ, tumor necrosis factor-α, interleukin (IL)-4 and IL-2, were detected in ConA-treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor-related apoptosis-inducing ligand and caspase-3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA-induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis.

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Future Perspective: Immunomodulatory Therapy for Autoimmune Hepatitis

Cited by 4 publications

References 46 publications

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis

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