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Beneficial Role of Rapamycin in Experimental Autoimmune Myositis.doc

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Beneficial Role of Rapamycin in Experimental Autoimmune Myositis

BeneficialRoleofRapamycininExperimental AutoimmuneMyositis NicolasPrevel1*.,YvesAllenbach4.,DavidKlatzmann1,2,3,4,BenoitSalomon1,3,OlivierBenveniste4 1UPMC Univ Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3); F-75005, Paris, France, 2CNRS, UMR 7211, Immunology-Immunopathology- Immunotherapy (I3); F-75005, Paris, France, 3INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy(I3); F-75005, Paris, France, 4AP-HP, Ho?pital Pitie′- Salpe?trie`re,Biotherapy(CIC-BTi)andInflammation-Immunopathology-Biotherapydepartment(I2B),F-75651,Paris,France Abstract Introduction:Wedevelopedanexperimentalautoimmunemyositis(EAM)mousemodelofpolymyositiswhereweoutlined the role of regulatory T (Treg) cells. Rapamycin, this immunosuppressant drug used to prevent rejection in organ transplantation,isknowntospareTreg.Ouraimwastotesttheefficacyofrapamycin invivointhisEAMmodelandto investigatetheeffectsofthedrugondifferentimmunecellsub-populations. Methods:EAMisinducedby3injectionsofmyosinemulsifiedinCFA.Micereceivedrapamycinduring25daysstartingone daybeforemyosinimmunization(preventivetreatment),orduring10daysfollowingthelastmyosinimmunization(curative treatment). Results:Underpreventiveorcurativetreatment,anincreaseofmusclestrengthwasobservedwithaparalleldecreaseof muscleinflammation,bothbeingwellcorrelated(R2=20.645,p,0.0001).Rapamycininducedageneraldecreaseinmuscle of CD4 and CD8 T cells in lymphoid tissues, but spared B cells. Among T cells, the frequency of Treg was increased in rapamycin treated mice in draining lymph nodes (16.962.2% vs. 9.361.4%, p,0.001), which were mostly activated regulatoryTcells(CD62Llow CD44 high:58.165.78%vs.33.167%,treatedvs.untreated,p,0.001).Inrapamycintreatedmice, inhibition of proliferation (Ki-67+) is more important in effector T cells compared to Tregs cells (p,0.05). Furthermore, during preventive treatment, rapamycin increased the levels of KLF2 transcript in CD44low CD62Lhigh naive T cell and in CD62Llow CD44high activ