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

ABSTRACT: 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 multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles 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(+)RoR?t(+)IL17(+) pathogenic T-regulatory cells (pgTreg), with a concomitant restoration of FoxP3(+)RoR?t(-)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. Furthermore, they implicate local manipulation of IL10 as a tractable therapeutic strategy to address the inflammatory sequelae associated with mucosal premalignancy.

SUBMITTER: Chung AY

PROVIDER: S-EPMC4322772 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Chung Allen Y AY Li Qingsheng Q Blair Sarah J SJ De Jesus Magdia M Dennis Kristen L KL LeVea Charles C Yao Jin J Sun Yijun Y Conway Thomas F TF Virtuoso Lauren P LP Battaglia Nicholas G NG Furtado Stacia S Mathiowitz Edith E Mantis Nicholas J NJ Khazaie Khashayarsha K Egilmez Nejat K NK

Cancer research 20140916 19

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 multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles ameliorates local and systemic disease to enhance survival. Mechanistic in ...[more]

PMID: 25228656

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Project description:Background: Arteriosclerosis (AS) involves arterial inflammation. Using macrophage-based drug delivery system, we aim to enhance local drug concentration, especially for short-lived anti-inflammatory molecules like interleukin-10. Our study intervenes in plaque progression by boosting IL-10 expression in macrophages lentiviral transfection and introducing these anti-inflammatory cells into Apoe-/- mice. Methods: We engineered RAW264.7 cells to overexpress IL-10 (referred to as IL-10M) using lentivirus vectors. Subsequent in vitro experiments were conducted to validate the effects and cellular functions of IL-10M. Fluorescence imaging allowed us to track the localization of IL-10M at atherosclerotic plaque sites after intravenous (IV) injection in Apoe-/- mice. We administered periodic injections of IL-10M at different stages of plaque progression in AS mice to assess its therapeutic impact on plaque advancement. Following the intervention, we collected samples from major organs and serum to evaluate the safety of IL-10M treatment. Results: Our engineered IL-10M exhibits robust IL-10 secretion, maintaining macrophage phagocytic function, and showing a tendency toward an M2 phenotype when exposed to inflammatory stimuli. Upon intravenous IL-10M administration, fluorescence imaging highlights precise plaque localization in both global and cross-sectional aortic regions. Regardless of whether intervention is initiated early or late in plaque progression, we observe significant reductions in plaque area and necrotic core. Importantly, IL-10M intervention does not impact the histological characteristics of the heart, liver, spleen, lungs, and kidneys, nor does it influence systemic inflammation levels. Conclusion: Our team has devised a novel anti-inflammatory protein delivery system utilizing modified macrophages, which exhibit a remarkable ability to target atherosclerotic plaques, resulting in the reduction of both plaque area and necrotic core. This innovative approach demonstrates favorable safety profiles and holds significant potential as a therapeutic strategy for managing atherosclerosis.

Dataset Information

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

Publications

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

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