title: 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(+)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. Furthermore, they implicate local manipulation of IL10 as a tractable therapeutic strategy to address the inflammatory sequelae associated with mucosal premalignancy.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Allen Y
authors.initials: AY
authors.lastname: Chung
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Blair
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, Albany, New York.
authors.forename: Magdia
authors.initials: M
authors.lastname: De Jesus
authors.affiliation: Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Dennis
authors.affiliation: Department of Surgical Pathology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Charles
authors.initials: C
authors.lastname: LeVea
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York. Department of Electrical and Computer Engineering, University of Florida, Gainesville, Florida.
authors.forename: Jin
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Conway
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Virtuoso
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Battaglia
authors.affiliation: Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University, Providence, Rhode Island.
authors.forename: Stacia
authors.initials: S
authors.lastname: Furtado
authors.affiliation: Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University, Providence, Rhode Island.
authors.forename: Edith
authors.initials: E
authors.lastname: Mathiowitz
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, Albany, New York.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mantis
authors.affiliation: Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York. nejat.egilmez@louisville.edu.
authors.forename: Nejat K
authors.initials: NK
authors.lastname: Egilmez
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000517:prevention & control*; D000284:Administration, Oral; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D016753:Interleukin-10 / Q000008:administration & dosage / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D017931:DNA Primers; D016753:Interleukin-10