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.
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 mouseTNFRII-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.
Authors: Roman Fischer; Tanja Padutsch; Valerie Bracchi-Ricard; Kayla L Murphy; George F Martinez; Niky Delguercio; Nicholas Elmer; Maksim Sendetski; Ricarda Diem; Ulrich L M Eisel; Richard J Smeyne; Roland E Kontermann; Klaus Pfizenmaier; John R Bethea Journal: Brain Behav Immun Date: 2019-06-17 Impact factor: 7.217
Authors: Wen-Yi Tseng; Yi-Shu Huang; Felix Clanchy; Kay McNamee; Dany Perocheau; Joy Ogbechi; Shue-Fen Luo; Marc Feldmann; Fiona E McCann; Richard O Williams Journal: Proc Natl Acad Sci U S A Date: 2019-10-09 Impact factor: 11.205
Authors: Fabian Richter; Sarah K Williams; Katharina John; Carina Huber; Camille Vaslin; Henri Zanker; Richard Fairless; Kira Pichi; Silke Marhenke; Arndt Vogel; Marie-Ann Dhaen; Stefanie Herrmann; Andreas Herrmann; Klaus Pfizenmaier; Heike Bantel; Ricarda Diem; Roland E Kontermann; Roman Fischer Journal: Front Immunol Date: 2021-07-07 Impact factor: 7.561
Authors: Valentina Pegoretti; Kathryn A Swanson; John R Bethea; Lesley Probert; Ulrich L M Eisel; Roman Fischer Journal: Oxid Med Cell Longev Date: 2020-05-12 Impact factor: 6.543
Authors: Roman Fischer; Maksim Sendetski; Tania Del Rivero; George F Martinez; Valerie Bracchi-Ricard; Kathryn A Swanson; Elizabeth K Pruzinsky; Niky Delguercio; Michael J Rosalino; Tanja Padutsch; Roland E Kontermann; Klaus Pfizenmaier; John R Bethea Journal: Proc Natl Acad Sci U S A Date: 2019-08-07 Impact factor: 11.205