title: Targeted IL-4 therapy synergizes with dexamethasone to induce a state of tolerance by promoting Treg cells and macrophages in mice with arthritis.
abstract: F8-IL-4 is a recently developed immunocytokine that delivers IL-4 to sites of inflammation by targeting the neovasculature. We previously reported that F8-IL-4, in combination with dexamethasone (DXM), provides a durable therapy in mice with collagen-induced arthritis (CIA). Therefore, the objective of this study was to identify the mechanism by which IL-4 and DXM combination therapy provides long-lasting disease remission. F8-IL-4 alone attenuated inflammation in CIA and this was associated with increased TH 2 and decreased TH 17 cell numbers in the joints. Similarly, DXM alone had an antiinflammatory effect associated with lower TH 17 cell numbers. In both cases, these therapeutic benefits were reversed once treatment was stopped. On the other hand, combination therapy with F8-IL-4 plus DXM led to a synergistic increase in the percentage of regulatory T (Treg) cells and antiinflammatory macrophages in the arthritic joint and spleen as well as IL-10 levels in serum and spleen. The net result of this was a more pronounced attenuation of inflammation and, more importantly, protection from arthritis relapse post therapy retraction. In conclusion, F8-IL-4 plus DXM is a durable treatment for arthritis that acts by promoting Treg cells in a synergistic manner, and by producing a sustained increase in antiinflammatory macrophages.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Joanna Z
authors.initials: JZ
authors.lastname: Kawalkowska
authors.affiliation: Philochem Zurich, Otelfingen, Switzerland.
authors.forename: Teresa
authors.initials: T
authors.lastname: Hemmerle
authors.affiliation: Philochem Zurich, Otelfingen, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pretto
authors.affiliation: Philochem Zurich, Otelfingen, Switzerland.
authors.forename: Mattia
authors.initials: M
authors.lastname: Matasci
authors.affiliation: Philochem Zurich, Otelfingen, Switzerland.|Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000628:therapy; D003907:Dexamethasone / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000627:therapeutic use; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology / Q000627:therapeutic use*; D007596:Joints / Q000276:immunology / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D058990:Molecular Targeted Therapy; D013154:Spleen / Q000276:immunology / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C528643:F8 monoclonal antibody; C556062:IL10 protein, mouse; D018796:Immunoconjugates; D016753:Interleukin-10; D015847:Interleukin-4; D003907:Dexamethasone
keywords: Arthritis; Dexamethasone; IL-4; Macrophages; Tolerance