Anti-IL-13Rα2 therapy promotes recovery in a murine model of inflammatory bowel disease.

Autor: Karmele EP; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.; Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA., Pasricha TS; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Ramalingam TR; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Thompson RW; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Gieseck RL 3rd; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.; Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, USA., Knilans KJ; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Hegen M; Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, USA., Farmer M; Biomedicine Design, Pfizer Inc., Cambridge, MA, USA., Jin F; Biomedicine Design, Pfizer Inc., Cambridge, MA, USA., Kleinman A; 23andMe, Mountain View, CA, USA., Hinds DA; 23andMe, Mountain View, CA, USA., Almeida Pereira T; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., de Queiroz Prado R; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.; Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, USA., Bing N; Human Genetics, Pfizer Inc., Cambridge, MA, USA., Tchistiakova L; Biomedicine Design, Pfizer Inc., Cambridge, MA, USA., Kasaian MT; Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, USA., Wynn TA; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.; Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, USA., Vannella KM; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. kevin.vannella@nih.gov.
Jazyk: angličtina
Zdroj: Mucosal immunology [Mucosal Immunol] 2019 Sep; Vol. 12 (5), pp. 1174-1186. Date of Electronic Publication: 2019 Jul 15.
DOI: 10.1038/s41385-019-0189-6
Abstrakt: There continues to be a major need for more effective inflammatory bowel disease (IBD) therapies. IL-13Rα2 is a decoy receptor that binds the cytokine IL-13 with high affinity and diminishes its STAT6-mediated effector functions. Previously, we found that IL-13Rα2 was necessary for IBD in mice deficient in the anti-inflammatory cytokine IL-10. Here, we tested for the first time a therapeutic antibody specifically targeting IL-13Rα2. We also used the antibody and Il13ra2 -/- mice to dissect the role of IL-13Rα2 in IBD pathogenesis and recovery. Il13ra2 - /- mice were modestly protected from induction of dextran sodium sulfate (DSS)-induced colitis. Following a 7-day recovery period, Il13ra2 -/- mice or wild-type mice administered the IL-13Rα2-neutralizing antibody had significantly improved colon health compared to control mice. Neutralizing IL-13Rα2 to increase IL-13 bioavailability promoted resolution of IBD even if neutralization occurred only during recovery. To link our observations in mice to a large human cohort, we conducted a phenome-wide association study of a more active variant of IL-13 (R130Q) that has reduced affinity for IL-13Rα2. Human subjects carrying R130Q reported a lower risk for Crohn's disease. Our findings endorse moving anti-IL-13Rα2 into preclinical drug development with the goal of accelerating recovery and maintaining remission in Crohn's disease patients.
Databáze: MEDLINE
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