%0 Journal Article %1 Fischer2018 %A Fischer, Roman %A Proske, Marcel %A Duffey, Maëlle %A Stangl, Hubert %A Martinez, George F. %A Peters, Nathalie %A Kraske, Alexandra %A Straub, Rainer H. %A Bethea, John R. %A Kontermann, Roland E. %A Pfizenmaier, Klaus %D 2018 %J Arthritis & Rheumatology %K 2018 izi kontermann pfizenmaier %R 10.1002/art.40413 %T Selective activation of tumor necrosis factor receptor 2 induces anti-inflammatory responses and alleviates experimental arthritis %U https://doi.org/10.1002/art.40413 %X OBJECTIVES Regulatory T cells (Tregs) modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor 2 (TNFR2) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Tregs. Here, we investigated the therapeutic activity of a novel TNFR2 agonist in experimental arthritis and the role of different Treg subsets. METHODS A novel mouse TNFR2-selective fusion protein (EHD2-sc-mTNFR2 ) was generated by genetic engineering. Mouse T cells were incubated together with IL-2 and/or EHD2-sc-mTNFR2 and effects on Tregs were analyzed by flow cytometry. Then mice with collagen induced arthritis were treated with EHD2-sc-mTNFR2 or saline and therapeutic effect was monitored and characterized. RESULTS Selective activation of TNFR2 does expand both, CD4+ as well as CD8+ Tregs. Moreover, TNFR2 activation elevated the number of CD4+ CD25+ Tregs, but not CD8+ CD25+ Tregs, and increased the number of FoxP3-expressing cells in CD8+ Tregs, but not CD4+ Tregs, implying different mechanisms of TNFR2-induced expansion of diverse T cell subsets with suppressive activity. Using the collagen induced arthritis model, we demonstrate that administration of the TNFR2 agonist EHD2-sc-mTNFR2 leads to the expansion of both CD4+ and CD8+ Tregs in vivo and induces anti-inflammatory responses that alleviate arthritis. CONCLUSIONS Summarizing, our data argue for the use of TNFR2-selective therapeutics as an effective approach in treating arthritic disease and possibly other inflammatory and autoimmune diseases. This article is protected by copyright. All rights reserved.

@article{Fischer2018, abstract = {OBJECTIVES Regulatory T cells (Tregs) modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor 2 (TNFR2) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Tregs. Here, we investigated the therapeutic activity of a novel TNFR2 agonist in experimental arthritis and the role of different Treg subsets. METHODS A novel mouse TNFR2-selective fusion protein (EHD2-sc-mTNFR2 ) was generated by genetic engineering. Mouse T cells were incubated together with IL-2 and/or EHD2-sc-mTNFR2 and effects on Tregs were analyzed by flow cytometry. Then mice with collagen induced arthritis were treated with EHD2-sc-mTNFR2 or saline and therapeutic effect was monitored and characterized. RESULTS Selective activation of TNFR2 does expand both, CD4+ as well as CD8+ Tregs. Moreover, TNFR2 activation elevated the number of CD4+ CD25+ Tregs, but not CD8+ CD25+ Tregs, and increased the number of FoxP3-expressing cells in CD8+ Tregs, but not CD4+ Tregs, implying different mechanisms of TNFR2-induced expansion of diverse T cell subsets with suppressive activity. Using the collagen induced arthritis model, we demonstrate that administration of the TNFR2 agonist EHD2-sc-mTNFR2 leads to the expansion of both CD4+ and CD8+ Tregs in vivo and induces anti-inflammatory responses that alleviate arthritis. CONCLUSIONS Summarizing, our data argue for the use of TNFR2-selective therapeutics as an effective approach in treating arthritic disease and possibly other inflammatory and autoimmune diseases. This article is protected by copyright. All rights reserved.}, added-at = {2018-02-01T14:30:30.000+0100}, author = {Fischer, Roman and Proske, Marcel and Duffey, Ma{\"{e}}lle and Stangl, Hubert and Martinez, George F. and Peters, Nathalie and Kraske, Alexandra and Straub, Rainer H. and Bethea, John R. and Kontermann, Roland E. and Pfizenmaier, Klaus}, biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2bc51d3b9c0039aa60271562d0d4adcb6/cristiano}, doi = {10.1002/art.40413}, interhash = {db024b580afdd258e31210e74039b34f}, intrahash = {bc51d3b9c0039aa60271562d0d4adcb6}, issn = {23265191}, journal = {Arthritis {\&} Rheumatology}, keywords = {2018 izi kontermann pfizenmaier}, month = jan, pmid = {29342501}, timestamp = {2019-01-17T12:27:11.000+0100}, title = {{Selective activation of tumor necrosis factor receptor 2 induces anti-inflammatory responses and alleviates experimental arthritis}}, url = {https://doi.org/10.1002/art.40413}, year = 2018 }