Oral IL-10 nanoparticles alleviate polyposis via site-specific neutralization of pathogenic T-regulatory cells.

摘要

The immunomodulatory cytokine interleukin-10 (IL-10) is essential for maintaining immune homeostasis at mucosal surfaces. The therapeutic potential of applying IL-10 towards the treatment of inflammation-driven diseases has, however, been limited by the short half-life of this cytokine, the pleiotropic nature of its effects, and the inability to target it to mucosal surfaces in a controllable and sustainable fashion.;Here, we will show that in the inflammation-driven APCmin mouse model of spontaneous gastrointestinal polyposis, orally-administered IL-10 nanoparticles (NPs) broadly recondition local intestinal immune environments and ameliorate established colitis. APCmin mice, when orally gavaged with IL-10 NPs, manifest reduced polyp burden and less aggressive intestinal pathology. Chronic oral IL-10 NP therapy alleviated constitutional symptoms, corrected fatal anemia and extended natural lifespan in experimental animals.;The efficacy of therapy was determined to be partially dependent on the neutralizing effect of IL-10 on pathogenic FoxP3+RORgammat+IL-17A+ T-regulatory cells (pgTregs). In response to IL-10 NP therapy, pgTregs lost the potential to produce interleukin 17A (IL-17A) and became reprogrammed in situ to more effectively suppress Th17-mediated intestinal inflammation. Adoptive transfer of neutralized Tregs into naive (untreated) APCmin mice reduced intestinal IL-17A secretion and was sufficient to partially transfer IL-10 NP anti-inflammatory and anti-polypotic effect.