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We previously reported that F8\u2010IL\u20104, in combination with dexamethasone (DXM), provides a durable therapy in mice with collagen\u2010induced arthritis (CIA). Therefore, the objective of this study was to identify the mechanism by which IL\u20104 and DXM combination therapy provides long\u2010lasting disease remission. F8\u2010IL\u20104 alone attenuated inflammation in CIA and this was associated with increased T<jats:sub>H<\/jats:sub>2 and decreased T<jats:sub>H<\/jats:sub>17 cell numbers in the joints. Similarly, DXM alone had an antiinflammatory effect associated with lower T<jats:sub>H<\/jats:sub>17 cell numbers. In both cases, these therapeutic benefits were reversed once treatment was stopped. On the other hand, combination therapy with F8\u2010IL\u20104 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\u201010 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\u2010IL\u20104 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.<\/jats:p>","DOI":"10.1002\/eji.201546221","type":"journal-article","created":{"date-parts":[[2016,2,27]],"date-time":"2016-02-27T14:48:24Z","timestamp":1456584504000},"page":"1246-1257","source":"Crossref","is-referenced-by-count":20,"title":["Targeted IL\u20104 therapy synergizes with dexamethasone to induce a state of tolerance by promoting Treg cells and macrophages in mice with arthritis"],"prefix":"10.1002","volume":"46","author":[{"given":"Joanna Z.","family":"Kawalkowska","sequence":"first","affiliation":[{"name":"Kennedy Institute of Rheumatology University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Hemmerle","sequence":"additional","affiliation":[{"name":"Philochem Zurich  Otelfingen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pretto","sequence":"additional","affiliation":[{"name":"Philochem Zurich  Otelfingen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Matasci","sequence":"additional","affiliation":[{"name":"Philochem Zurich  Otelfingen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Neri","sequence":"additional","affiliation":[{"name":"Philochem Zurich  Otelfingen Switzerland"},{"name":"Department of Chemistry and Applied Biosciences ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard O.","family":"Williams","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37346"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.4049\/jimmunol.159.11.5687","article-title":"Suppression of collagen\u2010induced arthritis by continuous administration of IL\u20104","volume":"159","author":"Horsfall A. 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