. Thelong-termgoalofourresearchistodevelopbetterstrategiestomanipulateinteractionsbetween dystrophicmuscleandtheimmunesystem,sothatthepathologyofDuchennemusculardystrophy(DMD)can bereduced.Asourknowledgeoftheinteractionsbetweentheimmunesystemanddystrophicmusclehas grown,severaldistinctmechanismsthroughwhichimmunecellspromotedamageofdystrophicmusclehave beenidentified.However,wehavealsolearnedthatspecificpopulationsofimmunecells,includingsome macrophagesubpopulationsandregulatoryT-cells,promotemusclegrowthandregenerationinmuscular dystrophy.Becausetheactivation,phenotypeandfunctionofimmunecellsthataffectmusculardystrophyare stronglyinfluencedbycostimulatorysignalsthatareexchangedbetweenmyeloidcellsandlymphoidcells, interventionsthattargetcostimulatorypathwayshavethecapacitytoinfluencethebalancebetween detrimentalandpro-regenerativeprocessesthataremediatedbyimmunecellsindystrophicmuscle. CytotoxicT-lymphocyte-associatedprotein4(CTLA4)isaparticularlyimportantcostimulatorymoleculethat influencesinteractionsbetweenimmunecells.ManipulationofCTLA4availabilitytomediatesignalingbetween myeloidandlymphoidcellsgreatlyinfluencesthemagnitudeandqualityoftheimmuneresponsetodiseased tissue.Ourpreliminaryfindingssupportthehypothesisthatadministrationofarecombinantfusionprotein containingCTLA4profoundlyinfluencestheimmuneresponsetodystrophicmuscleandreducesmuscle damage.Intheinvestigationproposedhere,wewilltestthathypothesis,determinethemechanismsthrough whichCTLA4-mediatedinterventionsaffectmusculardystrophyandevaluatethesafetyandefficacyoflong- termadministrationofexogenousCTLA4inthemdxmousemodelofDMD.
Aim1. TestthehypothesisthattreatmentswithCTLA4-immunoglobinfusionprotein(CTLA4-Ig)producelong- termreductionsinmusclepathologyandimprovefunctioninmousemodelsofDMD.
Aim2. TestthehypothesisthatCTLA4-Igactsonbothlymphoidandmyeloidcellstoreducemuscleinjuryand inflammationandpromoteapro-regenerativeenvironmentindystrophicmuscle.
Aim3. Assesssafetyandlong-termeffectsofCTLA4-Igadministrationonimmunecellfunction. Together,thesefindingscanenableustodeterminewhetherCTLA4-Ig,adrugthatissafeandefficaciousfor thetreatmentofotherhumandiseases,canprovideasuccessful,newstrategyfortreatingDMD.
. Duchennemusculardystrophy(DMD)isaprogressive,lethal,muscle-wastingdiseasethatis influencedbyinteractionsbetweenthediseasedmuscleandtheimmunesystem.Inthis investigation,wewilltestwhethermanipulatingcommunicationsbetweenpopulationsof immunecellsprovidesasafeandeffectivetherapeuticstrategyfortreatingDMD.