Low‐dose anti‐<scp>CD</scp>3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice

Marceau, Gabriel; Yang, Roland; Lapierre, Pascal; Béland, Kathie; Álvarez, Fernando

doi:10.1111/liv.12498

Cited by 15 publications

(11 citation statements)

References 37 publications

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“…Therefore, most models of autoimmune hepatitis that target specific autoantigens are models of type 2 AIH and have targeted either CYP2D6 or FTCD or both. These models have used adenoviral [29–31] or plasmid [32–36] vectors to express type 2 AIH liver autoantigen (CYP2D6 and/or FTCD) in mice. One of these models of type 2 AIH is based on xenoimmunization of wild type C57BL/6 mice with a plasmid coding for a chimeric human CYP2D6 and FTCD gene [36].…”

Section: Introductionmentioning

confidence: 99%

“…In an experimental model of type 2 AIH, CD4 + Tregs have been found to influence the outcome of the disease [33, 34]. In this model of type 2 AIH, host factors were found to have a definite influence on liver injury encompassing both central and peripheral tolerance mechanisms [32–36]. Xenoimmunized C57BL/6 mice developed AIH but not 129 S/v mice after xenoimmunisation [33].…”

Section: Introductionmentioning

confidence: 99%

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Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis

Lapierre

Lamarre

2015

Journal of Immunology Research

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In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4+ regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4+ T cells to CD4+ regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4+ regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis

Lapierre

Lamarre

2015

Journal of Immunology Research

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“…In this model of type 2 AIH, T cell depletion using low-dose anti-CD3 antibodies was performed as a mean to induce remission (Figure 1 ) ( 35 ). The treatment, which reduces the number of circulating T lymphocytes by 50%, led to the disappearance of liver inflammatory infiltrates, normalization of serum aminotransferase levels, and reduced autoantibodies titers ( 35 ). In addition, residual liver-infiltrating T lymphocytes were no longer responsive to autoantigen stimulation, suggesting that these lymphocytes had been tolerized ( 35 ).…”

Section: Immunotherapiesmentioning

confidence: 99%

“…The treatment, which reduces the number of circulating T lymphocytes by 50%, led to the disappearance of liver inflammatory infiltrates, normalization of serum aminotransferase levels, and reduced autoantibodies titers ( 35 ). In addition, residual liver-infiltrating T lymphocytes were no longer responsive to autoantigen stimulation, suggesting that these lymphocytes had been tolerized ( 35 ). These data suggest that partial T cell depletion could lead to the restoration of tolerance to hepatic autoantigens.…”

Section: Immunotherapiesmentioning

confidence: 99%

Novel Immunotherapies for Autoimmune Hepatitis

et al. 2017

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Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects.

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“…Vaccination of mice with plasmids expressing a nucleoprotein from the lymphocytic choriomeningitis virus (LCMV) together with interleukin-12 (IL-12) resulted in periportal and lobular infiltrates in the liver, production of viral- and self-antigen reactive T-cells, antibodies against the nucleoprotein and liver injury [ 58 ]. A similar model involved vaccination of female mice with cytomegalovirus (CMV) plasmids expressing the antigenic regions of human cytochrome P450 2D6 (CYP2D6) and formiminotransferase cyclodeaminase (FTCD), both proteins targeted by autoantibodies in human type 2 AIH [ 59 , 60 ]. Vaccination of the animals resulted in aminotransferase abnormalities 4–7 months post-immunization, portal and lobular inflammatory infiltrates, liver-infiltrating CD4 + and CD8 + T-cells, B-cells and antibody production against liver-kidney microsome type 1 (LKM-1) and liver cytosol type 1 (LC1) proteins [ 38 ].…”

Section: Animal Models Of Aihmentioning

confidence: 99%

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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Low‐dose anti‐CD3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice

Abstract: We report that low dose αCD3 antibody administration is an effective treatment for AIH in an experimental model of type 2 AIH. These data suggest that αCD3 antibody therapy could be tested in clinical trials as a rescue therapy for patients with uncontrolled AIH.

Cited by 15 publications

References 37 publications

Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis

Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis

Novel Immunotherapies for Autoimmune Hepatitis

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

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