Effects of Natalizumab Treatment on Foxp3+ T Regulatory Cells 英文参考文献.docVIP

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Effects of Natalizumab Treatment on Foxp3+ T Regulatory Cells 英文参考文献.doc

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EffectsofNatalizumabTreatmentonFoxp3TRegulatoryCells英文参考文献

EffectsofNatalizumabTreatmentonFoxp3+T RegulatoryCells Max-PhilippStenner1.,AnneWaschbisch1.¤a,DorotheaBuck1¤b,SebastianDoerck1,HermannEinsele2, KlausV.Toyka1,HeinzWiendl1* 1DepartmentofNeurology,Julius-MaximiliansUniversity,Wuerzburg,Germany,2DepartmentofInternalMedicineII,Julius-MaximiliansUniversity,Wuerzburg,Germany Abstract Background:Natalizumab,amonoclonalhumanizedantibodytargetingthealpha-4chainofverylateactivationantigen4 (VLA-4) exerts impressive therapeutic effects in patients withrelapsing-remitting multiple sclerosis. Our objective was to studyimpactsofNatalizumabtherapyonFoxp3+Tregulatorycells(Tregs)inmultiplesclerosis(MS)patients. Methodology:AcombinedapproachofinvitroandexvivoexperimentsusingTcellsisolatedfromtheperipheralbloodof healthydonorsandNatalizumabtreatedMSpatientswaschosen.WedeterminedbindingofNatalizumabanditseffectson thefrequency,transmigratorybehaviourandsuppressivefunctionofTregs. Principal Findings: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non- regulatoryandregulatorycells.AlbeitFoxp3+TregshadlowerlevelsofCD49d,Natalizumabblockedthetransmigrationof Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25 high CD127 conditions.Furthermore,theimpairedfunctionofTregsinMSpatientsisnotrestoredbyNatalizumabtreatment. low Foxp3 Tregs under in vitro + Conclusions:WeprovideafirstdetailedanalysisofNatalizumabeffectsontheregulatoryTcellpopulation.Ourprospective studyshowsthatFoxp3+TregsexpresslowerlevelsofVLA-4andbindlessNatalizumab.Wefurthertheunderstandingof the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeuticeffectsofthemonoclonalantibodyarelargelyindependentofalterationsinTregfrequencyorfunction. Citation:StennerM-P,WaschbischA,BuckD,DoerckS,EinseleH,etal.(2008)EffectsofNatalizumabTreatm