Technical Advance: Function and efficacy of an α4‐integrin antagonist using bioluminescence imaging to detect leukocyte trafficking in murine experimental colitis

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: DSS colitis;    small molecule inhibitors;   

DOI  :  10.1189/jlb.0909627

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

LeukocytetraffickingisatherapeutictargetinIBD.Theintegrinsα4β7andα4β1regulateleukocytemigrationintotissuesandlymphoidorgans.Currentstrategiesrelyonbiologics,suchasmAb,toinhibitleukocyterecruitment.Hereweshowtheinvivotherapeuticeffectsofasmallmoleculeα4‐integrinantagonist(GSK223618A)inaleukocyte‐traffickingmodelandamurinemodelofcolitis.LeukocytesisolatedfromMLNsoftransgenicβ‐actin‐luc+micewereinjectedi.v.intorecipientswithDSS‐inducedcolitis.Recipientmicewereorallygavagedwithvehicleoranα4‐integrinantagonist1hpre‐adoptivetransfer,followedbybioluminescencewholebodyandexvivoorganimaging4hpost‐transfer.Toconfirmitstherapeuticeffect,theα4‐integrinantagonistwasgivenorallytwicedailyfor6daystomicewithDSS‐inducedcolitis,startingonDay3.Clinical,macroscopic,andhistologicalsignsofinflammationwereassessedandgene‐expressionprofilesanalyzed.Usingbioluminescenceimaging,wetrackedandquantifiedleukocytemigrationtotheinflamedgutanddemonstrateditsinhibitionbyasmallmoleculeα4‐integrinantagonist.Additionally,thetherapeuticeffectoftheantagonistwasconfirmedinDSS‐inducedcolitisintermsofclinical,macroscopic,andhistologicalsignsofinflammation.Geneexpressionanalysissuggestedenhancementoftissuehealingincompound‐treatedanimals.Inhibitionofleukocytetraffickingusingsmallmoleculeintegrinantagonistsisapromisingalternativetolargemoleculebiologics.Furthermore,invivobioluminescenceimagingisavaluablestrategyforpreclinicalevaluationofpotentialtherapeuticsthattargetleukocytetraffickingininflammatorydiseases...

【 授权许可】

CC BY