Severe combined immunodeficient mice - Wikipedia

SCID Mice and HIV Severecombinedimmunodeficientmice FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch MiceusedintheresearchofhumandiseaselikeAIDS Micewithseverecombinedimmunodeficiency(SCIDs)areoftenusedintheresearchofhumandisease.Humanimmunecellsareusedtodevelophumanlymphoidorganswithintheseimmunodeficientmice,andmanydifferenttypesofSCIDmousemodelshavebeendeveloped.Thesemiceallowresearcherstostudythehumanimmunesystemandhumandiseaseinasmallanimalmodel.[1] Contents 1Discovery 2Types 3Useinresearch 4SCIDMiceandHIV 5Notes Discovery[edit] ThemutationcausingSCIDsinmicewasdiscoveredbyMelvinandGayleBosmain1983[1]intheCB/17mouseline.[2]SCIDsoccursinthesemiceduetoamutationinthegeneforproteinkinase,DNAactivated,catalyticpolypeptide(PRKDC),whichplaysaroleinrepairingdouble-strandedDNAbreaks.ThishasimplicationsforBandTcellreceptordevelopment,whichisdependentuponsuchdouble-strandedbreaksandsubsequentrepairsinordertorearrangeV,D,JorVandJsegments.[1] MicewithSCIDshavelymphocyteprogenitors,butthesecellsareunabletosurvivetomaturity.ThisresultsinalackofBandTcellsinthethymusandinthesecondarylymphoidorgans,suchasthespleenandlymphnodes.SomeSCIDmiceareabletoproducemonocytes,granulocytes,andredbloodcellsfromthehematopoieticstemcells(HSC)presentintheirbonemarrow.Duetotheirimmunodeficiency,micewithSCIDsoftendieyoungifnotkeptunderextremelysterileconditions.[1] TheabsenceoffunctionalBcellsresultsinanorganismthatisunabletoproduceantibodies.ThisfailuretocreateantibodiespreventsmostSCIDmicefromrejectingnon-selftissues.SomeSCIDmiceareshowntorejectskingrafts,soithasbeenproposedthatthisdiseasearisesfromaleakymutation,meaningthatsomemicewithSCIDsdoinfacthaveasomewhatfunctionaladaptiveimmunesystem.[1] Types[edit] TherearemanytypesofSCIDmiceusedbyresearchersatpresent.SomeexamplesincludeSCID-huThy/Livmice,whicharegivenhumanfetalthymusandlivercells,hu-SRC-SCIDmice,whichareimplantedwithhumanhematopoieticstemcells(HSC),andhu-PBL-SCIDmice,inwhichhumanperipheralbloodmononuclearcellshavebeeninjected.[3]Eachlineofmousehasdifferentfunctionalandnonfunctionalcells,makingeachsuitedfordifferentexperiments.[2] Inparticular,ithasbeenobservedthatSCIDmicewithanaddedmutationforinterleukin-2receptorcommongammachain(IL2Rγ)arebetterabletoaccepttransplantationofhumanHSCandcreatehumanBandTcells.[3][4]StudiessuchasthoseconductedbyItoetal.havefoundthatnon-obesediabetic(NOD)SCIDIL2Rγmiceareevenbettersuitedasmodelsfortissuetransplantsfromnon-selforganismsduetotheirlowerrateofrejectionofhumancells.[5]NOD/SCIDIL2Rγmicehavealsobeenusedtostudyhumanmelanoma.[6] Useinresearch[edit] SCIDmicecanservemanyfunctionsinresearch,particularlyinthestudyofhumanphysiologyanddisease.[7]Thestudyofhumanphysiologyinhumanmodelsisoftenmadeimpossibleduetoethicallimitations,highfinancialexpense,andlowavailabilityofmodelenvironments.Furthermore,resultsgleanedfromthestudyofhumancellsexvivomaynotbeindicativeoftheirfunctionsinvivo.[3]Duetotheirimmunodeficientstate,SCIDmiceareabletoaccepthumanhematopoieticstemcellsharvestedfromhumanbonemarroworthymus.Thiscanleadtothedevelopmentofhumanadaptiveimmunecells,suchasBandTlymphocytes,withinSCIDmice,andforsubsequentstudyofhumancellsinvivo.[1] SCIDmicehaveallowedforincreasedresearchonawiderangeoftopics,includingthedevelopmentandpluripotencyofhumanHSC,[1]human-specificdiseasesandtheirinteractionswiththehumanimmunesystem,[8]vaccination,[9]andcancer.[3]SCIDmicewithhumanimmunecellsareabletorespondtopathogenssuchasvirusesandcreateantibodiesagainstthem,whichhashelpedscientistsbetterunderstandhowthehumanimmunesystemprotectsagainstpathogeninfection.Forexample,theyhavebeenusedtostudyDenguevirusandmalaria,aswellastoassesstheefficacyofdrugsthattargetthesediseases.[3] ItisimportanttonotethattheuseofSCIDmicehasbeenquestionedasamodelforstudyingthehumanimmunesystem.Somestudieshavesuggestedthatafteraperiodoftime,humanTcellsintheimmunocompromisedmicebecomeanergic,meaningthattheynolongerrespondtostimuli.Thus,thesemicemaybeabletohostahumanimmunesystem,butonethatmaynotbefunctioningproperly.[2] SCIDMiceandHIV[edit] ImmunecompromisedmicehavebecomeofparticularinterestforstudyingtheHumanImmunodeficiencyVirus(HIV),howitinteractswiththehostinhumanlymphoidorgans,aswellashowtreatmentsworkinvivo.[7]WhileHIVnormallycannotinfectmice,[1]SCIDmicehavebeenusedtostudyHIV.[2]PriortotheuseofhumanizedSCIDmice,apemodelswereusedtostudyHIVduetotheirgeneticsimilaritytohumans.However,duetotheendangeredstatusofchimps,thecostofmaintainingthem,andtheslightdifferencesbetweenhumanandchimpinteractionswithHIV,humanizedmicehavebeenacceptedasamoreeffectivemodelorganismforthestudyofthisdisease.[2] NOD/SCIDmicecanbetransplantedwithhumanfetalliver,bone,thymus,andlymphoidcellsfrombloodtransplants,leadingtotheformationofhumanimmunecells,suchasBandTcells,withinthemice.[9]ThesemicearetheninfectedwiththevirusandresearchersareabletostudyhowHIVattacksthehumanlymphocytesandcausesacquiredimmunodeficiencysyndrome(AIDS)overtime.[2]Furthermore,humanizedmousemodelscanalsobeusedtotestpotentialtherapiesforthisdisease,includinggene-basedtherapies.[3] Notes[edit] ^abcdefghOwen,Judith;Punt,Jenni;Stranford,Sharon(2013).KubyImmunology.NewYork:W.H.FreemanandCompany. ^abcdefVanDuyne,Rachel;Pedati,Caitlin(2009)."Theutilizationofhumanizedmousemodelsforthestudyofhumanretroviralinfections".Retrovirology.6:76.doi:10.1186/1742-4690-6-76.PMC 2743631.PMID 19674458. ^abcdefBrehm,Michael;Shultz,Leonard(2010)."HumanizedMouseModelstoStudyHumanDiseases".HHSAuthorManuscripts.17:120–5.doi:10.1097/MED.0b013e328337282f.PMC 2892284.PMID 20150806. ^Brehm,Michael;Cuthbert,Amy(2010)."Parametersforestablishinghumanizedmousemodelstostudyhumanimmunity:AnalysisofhumanhematopoieticstemcellengraftmentinthreeimmunodeficientstrainsofmicebearingtheIL2rγnullmutation".ClinicalImmunology.135:84–98.doi:10.1016/j.clim.2009.12.008.PMC 2835837.PMID 20096637. ^Ito,Mamoru;Hiramatsu,Hidefumi(2002)."NOD/SCID/IL2Rγnullmouse:anexcellentrecipientmousemodelforengraftmentofhumancells".Blood.100:3175–3182.doi:10.1182/blood-2001-12-0207.PMID 12384415. ^Karageorgis,Anastassia;Micaël,Claron(2017)."SystemicDeliveryofTumor-TargetedBax-DerivedMembrane-ActivePeptidesfortheTreatmentofMelanomaTumorsinaHumanizedSCIDMouseModel".MolecularTherapy.25(2):534–546.doi:10.1016/j.ymthe.2016.11.002.PMC 5368406.PMID 28153100. ^abMcCune,Joseph(1996)."DevelopmentandapplicationsoftheSCID-humousemodel".SeminarsinImmunology.8(4):187–196.doi:10.1006/smim.1996.0024. ^Fanelli,Alex(2016)."XenograftingandXenotransplantation".Retrieved7January2018. ^abUchida,T;et al.(May2017)."UsefulnessofhumanizedcDNA-uPA/SCIDmiceforthestudyofhepatitisBvirusandhepatitisCvirusvirology".JGenVirol.98(5):1040–1047.doi:10.1099/jgv.0.000726.PMID 28141486. 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