1. Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis.
- Author
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Fischer, Roman, Proske, Marcel, Duffey, Maëlle, Stangl, Hubert, Martinez, George F., Peters, Nathalie, Kraske, Alexandra, Straub, Rainer H., Bethea, John R., Kontermann, Roland E., and Pfizenmaier, Klaus
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DRUG therapy for arthritis , *PHYSIOLOGIC salines , *ANIMAL experimentation , *AUTOIMMUNE diseases , *CELL receptors , *COLLAGEN , *FLOW cytometry , *GENE expression , *GENETIC engineering , *INFLAMMATION , *INFLAMMATORY mediators , *INTERLEUKIN-2 , *MICE , *T cells , *IN vivo studies , *TUMOR necrosis factors , *PHARMACODYNAMICS , *THERAPEUTICS - Abstract
Objective: Treg cells modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor II (TNFRII) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Treg cells. The purpose of the present study was to investigate the therapeutic activity of a novel TNFRII agonist in experimental arthritis as well as the role of different Treg cell subsets. Methods: A novel mouse TNFRII–selective fusion protein (EHD2‐sc‐mTNFR2) was generated by genetic engineering. Mouse T cells were incubated together with interleukin‐2 and/or EHD2‐sc‐mTNFR2, and the effects on Treg cells were analyzed by flow cytometry. Mice with collagen‐induced arthritis (CIA) were treated with EHD2‐sc‐mTNFR2 or saline, and the therapeutic effects were monitored and characterized. Results: Selective activation of TNFRII was found to expand both CD4+ and CD8+ Treg cells. Moreover, TNFRII activation elevated the number of CD4+CD25+ and CD8+CD25+ Treg cells and increased the number of FoxP3‐expressing cells in CD8+, but not CD4+, Treg cells, indicating different mechanisms of TNFRII‐induced expansion of diverse T cell subsets with suppressive activity. In the CIA model, we demonstrated that administration of the TNFRII agonist EHD2‐sc‐mTNFR2 led to the expansion of both CD4+ and CD8+ Treg cells in vivo and induced antiinflammatory responses that alleviated arthritis. Conclusion: Our findings support the use of TNFRII‐selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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