Integrative omics and phase IIa clinical trial identify TNF as key node in autoimmune hepatitis

Area of Science:

• Immunology
• Hepatology
• Computational Biology

Background:

• Autoimmune hepatitis (AIH) presents significant mortality risks and adverse effects from current non-specific immunosuppressive therapies.
• There is a critical need for targeted treatments that address the underlying mechanisms of AIH.

Purpose of the Study:

• To map the spatial and molecular immune network driving autoimmune hepatitis.
• To validate tumor necrosis factor (TNF) as a therapeutic target in a clinical trial for AIH.

Main Methods:

• Utilized computational modeling, multi-omics analyses, and functional experiments to characterize the AIH immune landscape.
• Conducted a phase IIa, steroid-free, open-label clinical trial using infliximab (a TNF-targeting antibody) in AIH patients.

Main Results:

• Identified IL-15 and TNF as key mediators promoting CD8+ T cell cytotoxicity and proliferation in AIH.
• Demonstrated that TNF from CD4+ T cells licenses cytotoxic activity and enhances hepatocyte adhesion molecule expression, making them targets.
• The clinical trial showed infliximab effectively treated AIH without steroids.

Conclusions:

• Elucidated the central role of TNF within the AIH immune network.
• Established TNF as a viable therapeutic target, supporting the development of novel, steroid-free treatments like infliximab for autoimmune hepatitis.