Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice 英文参考文献.docVIP

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Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice 英文参考文献.doc

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Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice 英文参考文献

RapidRegulatoryT-CellResponsePreventsCytokine StorminCD28SuperagonistTreatedMice TeaGogishvili1.,DanielaLangenhorst1.,FredLu¨hder2.,FernandoElias1,KarinElflein1,KevinM. Dennehy1,3,RalfGold4,ThomasHu¨nig1* 1Institute for Virology and Immunobiology, University of Wu¨rzburg, Wu¨rzburg, Germany, 2Institute for Multiple Sclerosis Research, University of Go¨ttingen and Gemeinnu¨tzige Hertie-Stiftung, Go¨ttingen, Germany, 3Department of Immunology, Institute for Cell Biology, Eberhard Karls University, Tu¨bingen, Germany, 4DepartmentofNeurologyatSt.JosefHospital,RuhrUniversityBochum,Bochum,Germany Abstract SuperagonisticCD28-specificmonoclonalantibodies(CD28SA)arehighlyeffectiveactivatorsofregulatoryT-cells(Tregcells) inrats,butafirst-in-mantrialofthehumanCD28SATGN1412resultedinanunexpectedcytokinereleasesyndrome.Usinga novelmouseanti-mouseCD28SA,were-investigatetherelationshipbetweenTregactivationandsystemiccytokinerelease. TregactivationbyCD28SAwashighlyefficientbutdependedonparacrineIL-2fromCD28SA-stimulatedconventionalT- cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic releaseofproinflammatorycytokines,indicatingthatinrodents,Tregcellseffectivelysuppresstheinflammatoryresponse. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroidprophylaxiswouldbecompatiblewithCD28SAinducedTregactivation.Weshowthatneithertheexpansion northefunctionalactivationofTregcellsisaffectedbyhigh-dosedexamethasonesufficienttocontrolsystemiccytokine release.Ourfindingswarnthatpreclinicaltestingofactivatingbiologicalsinrodentsmaymisscytokinereleasesyndromes duetotherapidandefficaciousresponseoftherodentTregcompartment,andsuggestthatpolyclonalTregactivationis feasibleinthepresenceofantiphlogisticcorticosteroidprophylaxis. Citation:GogishviliT,LangenhorstD,Lu¨hderF,EliasF,ElfleinK,etal.(2009)RapidRegulatoryT-CellResponsePreventsCytokineStorminCD28Superagon