New treatment options in autoimmune hepatitis

• Applicant: Professor Dr. Matthias Hardtke-Wolenski
• Subject Area: Gastroenterology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279617329

We aim to generate a new cellular therapy against autoimmune hepatitis (AIH) and test it in a clinically relevant mouse model. Autoimmune hepatitis is a chronic autoimmune inflammatory condition of liver tissue. Standard AIH therapy with steroids induces strong side effects, and as many as 20% of patients do not respond to the therapy. In addition, the majority of patients will experience disease relapse, and control of this disease requires life-long therapy. One reason for this outcome might be the preferential depletion of intrahepatic Tregs by steroid-based therapies. Steroid therapy suppresses the local immune response within the liver in AIH, but more Tregs than T effector cells were depleted. Therefore, the need for innovative therapies is urgent, specifically for those capable of strengthening intrahepatic immune regulation to potentially reestablish intrahepatic immune tolerance. We developed an experimental murine AIH (emAIH) model. These mice developed chronic hepatitis that closely resembled human AIH. Since we already addressed the issues of the etiology and pathophysiology in this model, we will focus on treatment options for AIH. For other autoimmune diseases, initial trials with adoptive Treg therapy have also been successfully performed. Furthermore, from our transplantation studies, we know that antigen-specific Tregs are very effective e.g. in prolonging graft survival. Due to biological and technical limitations, natural antigen-specific Tregs against autoantigens cannot be obtained in relevant cell numbers for therapy under GMP conditions.The specificity of Tregs can be altered by the expression of chimeric antigen receptors (CARs) on the cell surface. Therefore, we will generate CARs and then CAR-Tregs against a liver/hepatitis specific antigen. These CAR-Tregs are able to bridge the gap between the need for antigen-specific cells and the low number of antigen-specific Tregs in the T cell repertoire. Adoptive transfer of genetically engineered T cells has yielded promising results in humans, particularly in CD19-specific CAR-T cells in oncology patients. The in vitro generation of CAR-Tregs would, therefore, be a major step forward. These cells are expected to highly specific for a defined antigen directly related to hepatitis after transduction of the receptor. CAR-Tregs regulate autoreactive cells without side effects and enhance the healing effect. In contrast to transgenic T cell receptor-expressing Tregs, CAR-Tregs can be generated as an “off-the-shelf” therapeutic strategy with limited in vitro expansion time, as demonstrated in recent trials using CAR-modified T cells, in cancer and immunological studies, and by us and others to prevent graft rejection. Furthermore, our AIH model is adequate to support the development of new therapies and preventive procedures.

• DFG Programme: Research Grants