Therapeutically targeting indoleamine 2,3-dioxygenase 2 (IDO2) using a specific monoclonal antibody alleviates experimental arthritis, according to new findings published in Clinical Immunology. “Treatment with anti-IDO2 antibody inhibits autoreactive T and B cell responses and alleviates joint inflammation in the KRN preclinical model of autoimmune arthritis, fully recapitulating genetic IDO2 deficiency,” states Laura Mandik-Nayak, corresponding author of the study.

Credit: Macmillan Publishers Limited

The indoleamine 2,3-dioxygenase enzymes (IDO1 and IDO2) catalyze the rate-limiting step in the catabolism of tryptophan. “Through a series of genetic knockout studies in mice, we were able to distinguish distinct functions for IDO1 and IDO2, identifying IDO2, and not the better studied IDO1, as a proinflammatory mediator of autoimmune disease,” explains Lauren Merlo, lead author of the study. “However, small molecules that can be used to specifically target IDO2 in vivo have yet to be identified, so in the current study, we explored the use of a highly specific, monoclonal antibody therapy for IDO2,” she continues.

Treating mice with ... autoimmune arthritis with this anti-IDO2 antibody reduced the severity of disease

Treating mice with the KRN model of autoimmune arthritis with this anti-IDO2 antibody reduced the severity of disease compared with mice treated with a control antibody, regardless of whether the antibody was administered before or after the onset of disease. Merlo and colleagues reported similar findings in mice with collagen-induced arthritis. Using the KRN model to track autoreactive lymphocytes, the researchers pinpointed some of the mechanistic effects of anti-IDO2 antibody administration, including reduced T cell numbers in all subsets except regulatory T cells, and a decrease in IL-21 levels in mice treated with the anti-IDO2 antibody as compared with those given a control antibody.

As an intracellular molecule, IDO2 would not traditionally be considered a candidate target for antibody therapy. “Mechanistic studies showed that anti-IDO2 is able to access its intracellular target to exert its anti-arthritic effect by internalization via the FcγRIIb receptor on B cells,” explains Merlo. “This work validates IDO2 as a therapeutic target for rheumatoid arthritis and adds to a growing literature demonstrating antibody treatments that can target intracellular antigens to offer feasible and disease-selective approaches to treat disease,” adds Mandik-Nayak.