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New treatment options in autoimmune hepatitis

Subject Area Gastroenterology
Term from 2015 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 279617329
 
Final Report Year 2024

Final Report Abstract

This study provides important insights into the role of immune cells in the pathogenesis of autoimmune hepatitis (AIH), particularly highlighting the central role of CD4+ T cells in mediating liver inflammation. CD4+ T cells recognize liver-specific autoantigens and trigger an immune response that leads to hepatocyte destruction. The balance between effector T cells and regulatory T cells (Tregs) is crucial for controlling liver inflammation. Typically, Tregs suppress autoreactive T cells and prevent autoimmunity. However, in AIH, particularly following corticosteroid treatment, Tregs are depleted, allowing autoreactive T cells to cause persistent liver damage and inflammation. This imbalance between effector and regulatory T cells exacerbates the disease and leads to a more severe autoimmune response. B cells, which are traditionally associated with autoantibody production, have been shown to play a more complex role in AIH. This project explored B cell activity, particularly after splenectomy, and revealed that removing the spleen led to an increase in intrahepatic B cells. However, when anti-CD20 therapy was used to deplete B cells, there was no significant clinical improvement in the emAIH (experimental murine AIH) model. This suggests that while B cells contribute to the autoimmune environment by presenting antigens to T cells and secreting proinflammatory cytokines, their depletion alone does not halt disease progression. These findings emphasize that B cells play roles beyond autoantibody production in AIH, adding complexity to their involvement in the pathology of the disease. A particularly unexpected finding was the effect of splenectomy on AIH progression. It was initially hypothesized that removing the spleen, a major lymphoid organ, would reduce AIH severity. Instead, splenectomy exacerbated the disease with an increase in B cell infiltration and a significant decrease in Tregs within the liver. This revealed that the spleen plays a protective regulatory role in maintaining immune balance. The absence of the spleen leads to the disruption of immune homeostasis, contributing to more severe liver inflammation. Splenectomized mice also showed elevated levels of pro-inflammatory cytokines, such as IL-17, and increased apoptosis in liver cells, marked by a higher expression of caspase-3, a pro-apoptotic protein. This highlighted the spleen's role not only in regulating immune responses but also in maintaining the balance between pro- and anti-apoptotic signals in AIH. A significant breakthrough in this project was the development of a Treg-specific IL-2 therapy. In AIH, corticosteroid treatment, while effective at controlling inflammation, also depletes Tregs, exacerbating the imbalance between effector T cells and Tregs. To address this, low-dose IL-2 (ldIL-2) therapy was developed and tested to selectively expand the Treg population without stimulating the effector T cells. This study demonstrated that ldIL-2 treatment led to a substantial increase in intrahepatic Tregs, restoring immune tolerance in the liver, and significantly reducing liver inflammation, as evidenced by lower alanine transaminase levels. These findings suggest that Tregspecific IL-2 therapy could offer a promising new therapeutic approach for AIH patients, potentially reducing their dependence on long-term immunosuppressive drugs while restoring the immune balance in the liver.

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