Treg cell-based therapies challenges and persp.pdfVIP免费

ThetherapeuticpotentialofauniqueFOXP3+immuno­suppressivesubsetofregulatoryT(Treg)cellshasbeendemonstratedinvariouspreclinicalmodelsofgraft­versus­hostdisease(GVHD)1–3,solidorgantrans­plantation4,5,type1diabetesmellitus(T1D)6,7,systemiclupuserythematosus(SLE)8,inflammatoryboweldis­ease9,10andmultiplesclerosis(MS)11.Thishasstimulatedadvancesintheclinicaldevelopmentofadoptivecelltherapy(ACT)ofTregcellsintheclinic.Therearenowmorethan50activeandcompletedclinicaltrialstestingthesafetyandefficacyofTregcelltherapyforindicationssuchaskidneyorlivertransplantation,pemphigusvul­garis,SLE,inflammatoryboweldisease,autoimmunehepatitis,allergyandasthma12.AlthoughseparationandexpansionprotocolsfortheTregcellsvary,earlyclinicaltrialresultsreportmanufacturingsuccessandexcellentsafetyprofiles12–17.BroadeningthetherapeuticpotentialofTregcellACTwilldependontheuseofnoveltechno­logiestoalterthegenomeofthecellstoenhancefunctionalactivity,stability,persistenceandantigenspecificity.Numerouspreclinicalstudieshavedemonstratedthatantigen­specificTregcellsaremorepotentthanpolyclonalTregcellsinmodelsofT1D6,7,autoimmunecentralnerv­oussystemdisease18andtransplantation19–22.Moreover,antigen­specificTregcellspredominantlylocalizeatthesiteofantigenpresentation,decreasingtheriskofgeneralizedimmunosuppression.Thus,antigen­specificTregcellsmaybebothsaferandmoreefficientthanunselectedpoly­clonalTregcellsforACT.Becauseoftheirhighprecursorfrequency23,24,‘antigen­selected’humanTregcellswithdirectallospecificity,derivedfromthetransplantrecipi­ent,canbeefficientlyexpandedinvitrousingallogeneicantigen­presentingcells(APCs)fromthetransplantdonor25.Thisiscurrentlybeingevaluatedasacell­basedtherapyinseveralclinicaltrials26,27.However,Tregcellswithindirectallospecificityaswellasself­antigen­reactiveTregcellshaveaprecursorfrequencypredictedtobe1,000­foldto10,000­foldlowerthanthefrequencyofdirectalloreactiveTregcellsandhavenotbeeneffectivelyexpandedtodate23,28.Hence,alternativestrategiessuc...