Wanchoo, A. | Search bioRxiv

bioRxiv2021

Submandibular Injection of Indoleamine 2,3-Dioxygenase Galectin-3 Fusion Protein Inhibits and Prevents Periodontal Disease Progression Over 12 Weeks

AO_SCPLOWBSTRACTC_SCPLOWA major challenge in the treatment of chronic inflammatory diseases including periodontal diseases is the development of therapeutics to safely and specifically direct resolution of inflammation in a localized manner. Here we demonstrate the efficacy of a novel approach that addresses this unmet clinical need. Using an enzyme fusion protein of indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3) with tissue-anchored and thus localized immunomodulatory properties, we prevented and halted progression of induced polymicrobial periodontal disease. Efficacy was achieved with repeated treatment with IDO-Gal3 and was measured by effects on mandibular bone loss, soft tissue inflammation and local T cell plasticity. Specifically, both prophylactic and therapeutic administration of IDO-Gal3 were effective in reducing vertical mandibular bone loss and loss of mandibular bone volume and bone thickness induced by chronic polymicrobial infection. The efficacy observed is at least in part due to localized regulation of innate immune mediators such as IL-1{beta}, IL-6 and IL-8 as well as chemoattractants including IP-10, MCP-1 and MIP-1, while enhancing the expression of immunoregulatory cytokines such as IL-10. In addition, IDO-Gal3 treatment suppressed the induction of pathogenic CD4+Th1, CD8+Tc1, CD4+Th1/Th17, and CD8+Tc1/Tc17, while promoting the induction of homeostatic CD4+Th17, CD8+Tc17 and CD4+Tregs. Importantly, the efficacy of prophylactically and therapeutically administered IDO-Gal-3 is not dependent on bacterial burden as there were no appreciable effects on bacterial burden following either method of administration. Lastly, therapeutic rather than prophylactic administration of IDO-Gal3 is most effective in preventing mandibular bone loss through more robust innate and adaptive immune modulation. Together these and our previously published data indicate that therapeutic administration of IDO-Gal3 addresses the clinical needs for adjunctive therapeutics to treat active and/or established periodontal diseases.

immunology↗

bioRxiv2021

Galectin-anchored indoleamine 2,3-dioxygenase suppresses local inflammation

Summary paragraphChronic inflammation underlies the onset, progression and associated pain of numerous diseases.(1) Current anti-inflammatory treatments administered systemically are associated with moderate-to-severe side effects, while locally administered drugs have short-lived efficacy, and neither approach successfully modifies the underlying causality of disease.(2) We report a new way to locally modulate inflammation by fusing the enzyme indoleamine 2,3-dioxygenase 1 (IDO) to galectin-3 (Gal3). A general regulator of inflammation(3), IDO is immunosuppressive(4), catabolizing the essential amino acid tryptophan into kynurenine.(5) Recently we demonstrated that extracellular exogenous IDO regulates innate immune cell function(6), and envisioned delivering IDO into specific tissues would provide control of inflammation. However, proteins problematically diffuse away from local injection sites. Addressing this, we recently established that fusion to Gal3 anchors enzymes to tissues(7) via binding to extracellular glycans. Fusion protein IDO-Gal3 was retained in injected tissues and joints for up to a week or more, where it suppressed local inflammation in rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis. Amelioration of local inflammation, disease progression and inflammatory pain were concomitant with homeostatic preservation of tissues without global immune suppression. Thus, IDO-Gal3 presents a new concept of anchoring immunomodulatory enzymes for robust control of focal inflammation in multiple disease settings.

bioengineering↗