The immunomodulating enzyme indoleamine 2,3-dioxygenase 2 (IDO2) as a target for therapy in autoimmune disease

Abstract

Abstract The enzyme indoleamine 2,3-dioxygenase 2 (IDO2) is an important mediator of inflammatory autoimmune responses. Unlike its better-known counterpart, IDO1, which is thought to act primarily in an immunosuppressive manner, IDO2 acts to promote inflammation via a B-cell intrinsic mechanism. Prior work has demonstrated that genetic knockout of IDO2 can inhibit both autoantibody production and joint inflammation in the KRN.g7 murine model of arthritis. IDO2 played a similar role in driving inflammation in collagen induced arthritis and contact hypersensitivity models. Given the clear role of IDO2 in mediating autoimmunity, we have worked to find novel ways to target IDO2 in vivo. In addition to previous research successfully targeting the intracellular IDO2 protein with a novel monoclonal antibody, we have recently described an innovative, targeted DNA nanostructure-based siRNA-delivery system to specifically inhibit IDO2 function in B cells. Treatment of KRN mice with this B cell-directed anti-IDO2 siRNA nanotherapy reduced autoantibodies and attenuated arthritis, mimicking the phenotype seen with genetic knockouts. These data provided preclinical proof-of-concept that IDO2 could be effectively targeted as a treatment strategy in murine arthritis and suggested a similar strategy could be used target IDO2 in human RA. Similar to our findings using murine B cells, we found that IDO2 expression was elevated in B cells isolated from RA patients and could be silenced using anti-IDO2 siRNA in vitro. These data provide the first indication for the relevance of IDO2 in human RA and suggest nanoparticle delivery systems are a potential therapeutic strategy to inhibit IDO2 in RA patient B cells.