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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.

Original publication

DOI

10.1002/eji.201546221

Type

Journal article

Journal

European journal of immunology

Publication Date

05/2016

Volume

46

Pages

1246 - 1257

Addresses

Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Keywords

Joints, Spleen, Th2 Cells, Macrophages, Animals, Mice, Inbred DBA, Mice, Arthritis, Experimental, Dexamethasone, Anti-Inflammatory Agents, Interleukin-4, Interleukin-10, Antibodies, Monoclonal, Immunoconjugates, Drug Therapy, Combination, Immune Tolerance, Drug Synergism, T-Lymphocytes, Regulatory, Th17 Cells, Molecular Targeted Therapy