Oral interleukin-10 alleviates polyposis via neutralization of pathogenic T-regulatory cells

摘要

Immune dysregulation drives the pathogenesis of chronic inflammatory, autoimmune and dysplastic disorders. While often intended to address localized pathology, most immune modulatory therapies are administered systemically and carry inherent risk of multi-organ toxicities. Here we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally-administered microparticles of the interleukin IL-10 ameliorates local and systemic disease to enhance survival. Mechanistic investigations showed that the therapeutic benefit of this treatment derived from neutralization of disease-promoting FoxP3+RoRγt+IL17+ pathogenic T-regulatory cells (pgTreg), with a concomitant restoration of FoxP3+RoRγt-IL17- conventional T regulatory cells (Treg). These findings provide a proof-of-principle for the ability of an oral biologic to restore immune homeostasis at the intestinal surface. Further, they implicate local manipulation of IL-10 as a tractable therapeutic strategy to address the inflammatory sequelae associated with mucosal premalignancy.