Systemic Lupus Erythematosus (SLE) is a heterogeneous disease characterized by autoantibody production. Several new therapies have been designed to inhibit autoantibodies by interfering with B cell differentiation or survival, however these treatments are not always effective and there is a continuing need for new therapeutic strategies to address the underling causes of SLE. The studies in this proposal will investigate a new therapeutic strategy to block the autoimmune response by inhibition of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2). Using a combination of genetic and pharmacological studies in a preclinical model of arthritis, we demonstrated a critical role for IDO2 in driving B cell-mediated autoimmunity. Mechanistic investigations revealed that IDO2 was needed to activate T helper cells, generate pathogenic autoantibodies, and drive disease development. This led us to hypothesize that targeting IDO2 would also be an effective strategy to block the autoimmune response driving SLE. In this proposal, we will use a well-characterized preclinical model of SLE to examine the effectiveness of a newly developed IDO2 monoclonal antibody therapy in reducing the production of autoantibodies, inflammatory cytokines, and glomerulonephritis characteristic of SLE. If successful, this work could lead to a new strategy to prevent and treat autoantibody-mediated disease in SLE patients.