rapid regulatory t-cell response prevents cytokine storm in cd28 superagonist treated mice快速调节t细胞反应阻止细胞激素风暴在cd28 superagonist治疗老鼠.pdfVIP

Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice 1. 1. ¨ 2. 1 1 Tea Gogishvili , Daniela Langenhorst , Fred Luhder , Fernando Elias , Karin Elflein , Kevin M. 1,3 4 ¨ 1 Dennehy , Ralf Gold , Thomas Hunig * ¨ ¨ ¨ 1 Institute for Virology and Immunobiology, University of Wurzburg, Wurzburg, Germany, 2 Institute for Multiple Sclerosis Research, University of Gottingen and ¨ ¨ ¨ Gemeinnutzige Hertie-Stiftung, Gottingen, Germany, 3 Department of Immunology, Institute for Cell Biology, Eberhard Karls University, Tubingen, Germany, 4 Department of Neurology at St. Josef Hospital, Ruhr University Bochum, Bochum, Germany Abstract Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T- cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytok