Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes

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1、Proof-of-Concept,Randomized,ControlledClinicalTrialofBacillus-Calmette-GuerinforTreatmentofLong-TermType1Diabetes111111DeniseL.Faustman*,LimeiWang,YoshiakiOkubo,DouglasBurger,LiqinBan,GuotongMan,22333HuiZheng,DavidSchoenfeld,RichardPompei,JosephAvruch,Da

2、vidM.Nathan1TheImmunobiologyLaboratory,MassachusettsGeneralHospitalandHarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,2DepartmentofBiostatistics,MassachusettsGeneralHospital,Boston,Massachusetts,UnitedStatesofAmerica,3DiabetesUnit,Massach

3、usettsGeneralHospital,Boston,Massachusetts,UnitedStatesofAmericaAbstractBackground:Notargetedimmunotherapiesreversetype1diabetesinhumans.However,inarodentmodeloftype1diabetes,BacillusCalmette-Guerin(BCG)reversesdiseasebyrestoringinsulinsecretion.Specific

4、ally,itstimulatesinnateimmunitybyinducingthehosttoproducetumornecrosisfactor(TNF),which,inturn,killsdisease-causingautoimmunecellsandrestorespancreaticbeta-cellfunctionthroughregeneration.Methodology/PrincipalFindings:Translatingthesefindingstohumans,wea

5、dministeredBCG,agenericvaccine,inaproof-of-principle,double-blind,placebo-controlledtrialofadultswithlong-termtype1diabetes(mean:15.3years)atoneclinicalcenterinNorthAmerica.SixsubjectswererandomlyassignedtoBCGorplaceboandcomparedtoself,healthypairedcontr

6、ols(n=6)orreferencesubjectswith(n=57)orwithout(n=16)type1diabetes,dependingupontheoutcomemeasure.Wemonitoredweeklybloodsamplesfor20weeksforinsulin-autoreactiveTcells,regulatoryTcells(Tregs),glutamicaciddecarboxylase(GAD)andotherautoantibodies,andC-peptid

7、e,amarkerofinsulinsecretion.BCG-treatedpatientsandoneplacebo-treatedpatientwho,afterenrollment,unexpectedlydevelopedacuteEpstein-Barrvirusinfection,aknownTNFinducer,exclusivelyshowedincreasesindeadinsulin-autoreactiveTcellsandinductionofTregs.C-peptidele

8、vels(pmol/L)significantlyrosetransientlyintwoBCG-treatedsubjects(means:3.49pmol/L[95%CI2.95–3.8],2.57[95%CI1.65–3.49])andtheEBV-infectedsubject(3.16[95%CI2.54–3.69])vs.1.65[95%CI1.55–3.2]inreferencediabeticsubjects.thBCG-t