Antibody blockade of IL‐17 family cytokines in immunity to acute murine oral mucosal candidiasis

[摘要] AntibodiestargetingIL‐17Aoritsreceptor,IL‐17RA,areapprovedtotreatpsoriasisandarebeingevaluatedforotherautoimmuneconditions.Conversely,IL‐17signalingiscriticalforimmunitytoopportunisticmucosalinfectionscausedbythecommensalfungusCandidaalbicans,asmiceandhumanslackingtheIL‐17Rexperiencechronicmucosalcandidiasis.IL‐17A,IL‐17F,andIL‐17AFbindtheIL‐17RA‐IL‐17RCheterodimericcomplexanddeliverqualitativelysimilarsignalsthroughtheadaptorAct1.Here,weusedamousemodelofacuteoropharyngealcandidiasistoassesstheimpactofblockingIL‐17familycytokinescomparedwithspecificIL‐17cytokinegeneknockoutmice.Anti‐IL‐17Aantibodies,whichneutralizeIL‐17AandIL‐17AF,causedelevatedoralfungalloads,whereasanti‐IL‐17AFandanti‐IL‐17Fantibodiesdidnot.Notably,therewasacooperativeeffectofblockingIL‐17A,IL‐17AF,andIL‐17Ftogether.Terminationofanti‐IL‐17AtreatmentwasassociatedwithrapidC.albicansclearance.IL‐17F‐deficientmicewerefullyresistanttooropharyngealcandidiasis,consistentwithantibodyblockade.However,IL‐17A‐deficientmicehadlowerfungalburdensthananti‐IL‐17A‐treatedmice.Act1‐deficientmiceweremuchmoresusceptibletooropharyngealcandidiasisthananti‐IL‐17Aantibody‐treatedmice,yetanti‐IL‐17Aandanti‐IL‐17RAtreatmentcausedequivalentsusceptibilities.Basedonmicroarrayanalysesoftheoralmucosaduringinfection,onlyalimitednumberofgeneswereassociatedwithoropharyngealcandidiasissusceptibility.Insum,weconcludethatIL‐17Aisthemaincytokinemediatorofimmunityinmurineoropharyngealcandidiasis,butacooperativerelationshipamongIL‐17A,IL‐17AF,andIL‐17Fexistsinvivo.Susceptibilitydisplaysthefollowinghierarchy:IL‐17RA‐orAct1‐deficiency>anti‐IL‐17A+anti‐IL‐17Fantibodies>anti‐IL‐17Aoranti‐IL‐17RAantibodies>IL‐17Adeficiency...

[学科分类] 生理学

[关键词] fungal;Th17;IL‐17R;psoriasis;anticytokine therapy