Autoimmune diseases (AIDs) such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc) are chronic conditions marked by adaptive immune activation, autoantibody production, and organ inflammation. Targeting autoimmunity is key to breaking persistent inflammation and achieving sustained remission, reducing reliance on long-term anti-inflammatory or immunosuppressive therapy. Chimeric antigen receptor (CAR)-T cell therapy has demonstrated transformative potential for treating refractory autoimmune diseases, starting 2021 with CD19-directed construct achieving sustained drug-free remission in a patient with refractory SLE and extending therapeutic benefits to IIM and SSc. Given the exceptional results in terms of safety and efficacy, further case series and clinical studies followed. Clinical remission occurred within weeks of infusion, with biomarker normalization and immune reconstitution featuring naïve B cell populations.
Here, we propose a reverse translational approach that considers our patients as human model systems for studying successful remission. Our goal is to better explain the effects of treatment with CD19 CAR-T cells at the level of B and T cells as well as myeloid cells. We will characterize the effects of CD19 CAR-T cell therapy on the restoration of the B cell pool and in particular on the immunometabolism of memory and plasma B cell. We will also attempt to directly detect and visualize dsDNA-reactive B cells by immunostaining. Effects of therapy on T cell lineages will be determined at three selected time points (before, during and after CAR T cell therapy) by multicolour flow cytometry and TCR sequencing. Finally, monocyte polarization will be assessed during the course of therapy to understand the switch from pro-inflammatory to alternatively activated macrophages. The combination of these data will shed light on the molecular mechanisms underlying the achievement of remission in autoimmune inflammation.
Principal Investigators
Prof. Dr. rer. nat. Aline Bozec
Dr. med. Jule Bachl