Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes 英文参考文献.docVIP

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Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes 英文参考文献.doc

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Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes 英文参考文献

Proof-of-Concept,Randomized,ControlledClinicalTrial ofBacillus-Calmette-GuerinforTreatmentofLong-Term Type1Diabetes DeniseL.Faustman1*,LimeiWang1,YoshiakiOkubo1,DouglasBurger1,LiqinBan1,GuotongMan1, HuiZheng2,DavidSchoenfeld2,RichardPompei3,JosephAvruch3,DavidM.Nathan3 1The Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 2Department of Biostatistics,MassachusettsGeneralHospital,Boston,Massachusetts,UnitedStatesofAmerica,3DiabetesUnit,MassachusettsGeneralHospital,Boston,Massachusetts, UnitedStatesofAmerica Abstract Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunitybyinducingthehosttoproducetumornecrosisfactor(TNF),which,inturn,killsdisease-causingautoimmune cellsandrestorespancreaticbeta-cellfunctionthroughregeneration. Methodology/PrincipalFindings:Translatingthesefindingstohumans,weadministeredBCG,agenericvaccine,inaproof- of-principle,double-blind,placebo-controlledtrialofadultswithlong-termtype1diabetes(mean:15.3years)atoneclinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n=6) or reference subjects with (n=57) or without (n=16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patientsandoneplacebo-treatedpatientwho,afterenrollment,unexpectedlydevelopedacuteEpstein-Barrvirusinfection, aknownTNFinducer,exclusivelyshowedincreasesindeadinsulin-autoreactiveTcellsandinductionofTregs.C-peptide levels(pmol/L)significantlyrosetransientlyintwoBCG-treatedsubjects(means:3.49pmol/L[95%CI2