Autoimmune rheumatologic diseases
Immunomodulatory biologics for inflammation would greatly benefit from new retention strategies to localize suppression. We have developed a chimeric fusion protein incorporating novel approaches for both retention and suppression to induce potent, confined metabolic programming. Immunosuppressive indoleamine 2,3 dioxygenase (IDO), which depletes tryptophan through the kynurenine pathway, was fused to Galectin 3 (Gal3), which binds extracellular glycans and provides tissue anchoring. Using a luciferase-Gal3 fusion reporter, tissue retention was greatly prolonged for days to weeks, whereas native luciferase is not retained and undetectable by 24 h. IDO-Gal3 injected locally blocked inflammation in multiple models including local LPS-challenge and periodontal disease. Consistent with in vivo results, in vitro studies demonstrate exogenous supply of IDO conditions dendritic cells to a suppressive phenotype and blocks dendritic cell ability to stimulate T cells in antigen specific culture models.