Humanized mouse - Wikipedia

Hu-SRC-scid model Humanizedmouse FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Ahumanizedmouseisamousecarryingfunctioninghumangenes,cells,tissues,and/ororgans.Humanizedmicearecommonlyusedassmallanimalmodelsinbiologicalandmedicalresearchforhumantherapeutics. Ahumanizedmouseorahumanizedmousemodelisonethathasbeenxenotransplantedwithhumancellsand/orengineeredtoexpresshumangeneproducts,soastobeutilizedforgainingrelevantinsightsintheinvivocontextforunderstandingofhuman-specificphysiologyandpathologies.[1]Alotofourknowledgeaboutseveralhumanbiologicalprocesseshasbeenobtainedfromstudyinganimalmodelslikerodentsandnon-humanprimates.Inparticular,smallanimalssuchasmiceareadvantageousinsuchstudiesowingtotheirsmallsize,briefreproductivecycle,easyhandlingandduetothegenomicandphysiologicalsimilaritieswithhumans;moreover,theseanimalscanalsobegeneticallymodifiedeasily.Nevertheless,thereareseveralincongruenciesoftheseanimalsystemswiththoseofhumans,especiallywithregardtothecomponentsoftheimmunesystem.Toovercometheselimitationsandtorealizethefullpotentialofanimalmodelstoenableresearcherstogetaclearpictureofthenatureandpathogenesisofimmuneresponsesmountedagainsthuman-specificpathogens,humanizedmousemodelshavebeendeveloped.Suchmousemodelshavealsobecomeanintegralaspectofpreclinicalbiomedicalresearch.[2] Contents 1History 2Types 2.1Hu-PBL-scidmodel 2.2Hu-SRC-scidmodel 2.3BLT(bonemarrow/liver/thymus)model 3Establishedmodelsforhumandiseases 3.1Infectiousdiseases 3.2Cancers 3.3Autoimmunediseases 4Seealso 5References 6Furtherreading History[edit] Thediscoveryoftheathymicmouse,commonlyknownasthenudemouse,andthatoftheSCIDmouseweremajoreventsthatpavedthewayforhumanizedmicemodels.ThefirstsuchmousemodelwasderivedbybackcrossingC57BL/KaandBALB/cmice,featuringalossoffunctionmutationinthePRKDCgene.ThePRKDCgeneproductisnecessaryforresolvingbreaksinDNAstrandsduringthedevelopmentofTcellsandBcells.DysfunctionalPRKDCgeneleadstoimpaireddevelopmentofTandBlymphocyteswhichgivesrisetoseverecombinedimmunodeficiency(SCID).Inspiteoftheeffortsindevelopingthismousemodel,poorengraftmentofhumanhematopoieticstemcells(HSCs)wasamajorlimitationthatcalledforfurtheradvancementinthedevelopmenthumanizedmousemodels.[3]Thenextbigstepinthedevelopmentofhumanizedmicemodelscamewithtransferofthescidmutationtoanon-obesediabeticmouse.ThisresultedinthecreationoftheNOD-scidmicewhichlackedTcells,Bcells,andNKcells.Thismousemodelpermittedforaslightlyhigherlevelofhumancellreconstitution.Nevertheless,amajorbreakthroughinthisfieldcamewiththeintroductionofthemutantinterleukin2receptorα(IL2rα)geneintheNOD-scidmodel.ThisaccountedforthecreationoftheNOD-scid-γcnullmice(NCG,NSGorNOG)modelswhichwereportrayedtohavedefectiveinterleukinsIL-2,IL-4,IL-7,IL-9,andIL-15.ResearchersevolvedthisNSGmodelbyknockingouttheRAG1andRAG2genes(recombinationactivationgenes),resultingintotheRAGnullversionoftheNSGmodelthatwasdevoidofmajorcellsoftheimmunesystemincludingthenaturalkillercells,BlymphocytesandTlymphocytes,macrophagesanddendriticcells,causingthegreatestimmunodeficiencyinmicemodelssofar.Thelimitationwiththismodelwasthatitlackedthehumanleukocyteantigen.Inaccordancetothislimitation,the humanTcellswhenengraftedinthemice,failedtorecognizehumanantigen-presentingcells,whichconsequatedindefectiveimmunoglobulinclassswitchingandimproperorganizationofthesecondarylymphoidtissue.[4] Tocircumventthislimitation,thenextdevelopmentcamewiththeintroductionoftransgenesencodingforHLAIandHLAIIintheNSGRAGnullmodelthatenabledbuildoutofhumanT-lymphocyterepertoiresaswellastherespectiveimmuneresponses.[5] Types[edit] Engraftinganimmunodeficientmousewithfunctionalhumancellscanbeachievedbyintravenousinjectionsofhumancellsandtissueintothemouse.Thissectionhighlightsthevarioushumanizedmicemodelsdevelopedusingthedifferentmethods. Hu-PBL-scidmodel[edit] ThismodelisdevelopedbyintravenouslyinjectinghumanPBMCsintoimmunodeficientmice.Theperipheralbloodmononuclearcellstobeengraftedintothemodelareobtainedfromconsentedadultdonors.Theadvantagesassociatedwiththismethodarethatitiscomparativelyaneasytechnique,themodeltakesrelativelylesstimetogetestablishedandthatthemodelexhibitsfunctionalmemoryTcells.[6]Itisparticularlyveryeffectiveformodellinggraftvs.hostdisease.[5]ThemodellacksengraftmentofBlymphocytesandmyeloidcells.Otherlimitationswiththismodelarethatitissuitableforuseonlyinshort-termexperiments(<3months)andthepossibilitythatthemodelitselfmightdevelopgraftvs.hostdisease.[5] Hu-SRC-scidmodel[edit] Hu-SRC-scidmicearedevelopedbyengraftingCD34+humanhematopoieticstemcellsintoimmunodeficientmice.Thecellsareobtainedfromhumanfetalliver,bonemarrowor frombloodderivedfromtheumbilicalcord,[7]andengraftedviaintravenousinjection.Theadvantagesofthismodelarethatitoffersmultilineagedevelopmentofhematopoieticcells,generationofanaïveimmunesystem,andifengraftmentiscarriedoutbyintrahepaticinjectionofnewbornmicewithin72hoursofbirth,itcanleadtoenhancedhumancellreconstitution.Nevertheless,limitationsassociatedwiththemodelarethatittakesaminimumof10weeksforcelldifferentiationtooccur,itharborslowlevelsofhumanRBCs,polymorphonuclearleukocytes,andmegakaryocytes.[5] BLT(bonemarrow/liver/thymus)model[edit] TheBLTmodelisconstitutedwithhumanHSCs,bonemarrow,liver,andthymus.TheengraftmentiscarriedoutbyimplantationofliverandthymusunderthekidneycapsuleandbytransplantationofHSCsobtainedfromfetalliver.TheBLTmodelhasacompleteandtotallyfunctionalhumanimmunesystemwithHLA-restrictedTlymphocytes.Themodelalsocomprisesamucosalsystemthatissimilartothatofhumans.Moreover,amongallmodelstheBLTmodelhasthehighestlevelofhumancellreconstitution.[8] However,sinceitrequiressurgicalimplantation,thismodelisthemostdifficultandtime-consumingtodevelop.Otherdrawbacksassociatedwiththemodelarethatitportraysweakimmuneresponsestoxenobiotics,sub-optimalclassswitchingandmaydevelopGvHD.[5] Establishedmodelsforhumandiseases[edit] Severalmechanismsunderlyinghumanmaladiesarenotfullyunderstood.Utilizationofhumanizedmicemodelsinthiscontextallowsresearcherstodetermineandunravelimportantfactorsthatbringaboutthedevelopmentofseveralhumandiseasesanddisordersfallingunderthecategoriesofinfectiousdisease,cancer,autoimmunity,andGvHD. Infectiousdiseases[edit] Amongthehuman-specificinfectiouspathogensstudiedonhumanizedmicemodels,thehumanimmunodeficiencyvirushasbeensuccessfullystudied.[5]Besidesthis,humanizedmodelsforstudyingEbolavirus,[9]HepatitisB,[10]HepatitisC,[11]Kaposi'ssarcoma-associatedherpesvirus,[12]Leishmaniamajor,[13]malaria,[14]andtuberculosis[15]havebeenreportedbyvariousstudies. NOD/scidmicemodelsfordenguevirus[16]andvaricella-zostervirus,[17]andaRag2null𝛾cnullmodelforstudyinginfluenzavirus[18]havealsobeendeveloped. Cancers[edit] Onthebasisofthetypeofhumancells/tissuesthathavebeenusedforengraftment,humanizedmousemodelsforcancercanbeclassifiedaspatient-derivedxenograftsorcellline-derivedxenografts.[19]PDXmodelsareconsideredtoretaintheparentalmalignancycharacteristicsatagreaterextentandhencetheseareregardedasthemorepowerfultoolforevaluatingtheeffectofanticancerdrugsinpre-clinicalstudies.[19][20]Humanizedmousemodelsforstudyingcancersofvariousorganshavebeendesigned.AmousemodelforthestudyofbreastcancerhasbeengeneratedbytheintrahepaticengraftmentofSK-BR-3cellsinNSGmice.[21]Similarly,NSGmiceintravenouslyengraftedwithpatient-derivedAMLcells,[22]andthoseengrafted(viasubcutaneous,intravenousorintra-pancreaticinjections)withpatient-derivedpancreaticcancertumors[23]havealsobeendevelopedforthestudyofleukemiaandpancreaticcancerrespectively.Severalotherhumanizedrodentmodelsforthestudyofcancerandcancerimmunotherapyhavealsobeenreported.[24] Autoimmunediseases[edit] Problemsposedbythedifferencesinthehumanandrodentimmunesystemshavebeenovercomeusingafewstrategies,soastoenableresearcherstostudyautoimmunedisordersusinghumanizedmodels.NSGmiceengraftedwithPBMCsandadministeredwithmyelinantigensinFreund'sadjuvant,andantigen-pulsedautologousdendriticcellshavebeenusedtostudymultiplesclerosis.[25]Similarly,NSGmiceengraftedwithhematopoieticstemcellsandadministeredwithpristanehavebeenusedforstudyinglupuserythematosus.[26]Furthermore,NOGmiceengraftedwithPBMCshasbeenusedtostudymechanismsofallograftsrejectioninvivo.[27] Seealso[edit] Nudemouse SCIDmouse NOGmouse NSGmouse Mousemodelofcolorectalandintestinalcancer Mousemodelsofbreastcancermetastasis References[edit] ^StripeckeR,MünzC,SchuringaJJ,BissigKD,SoperB,MeehamT,et al.(July2020)."Innovations,challenges,andminimalinformationforstandardizationofhumanizedmice".EMBOMolecularMedicine.12(7):e8662.doi:10.15252/emmm.201708662.PMC 7338801.PMID 32578942. ^WalshNC,KenneyLL,JangalweS,AryeeKE,GreinerDL,BrehmMA,ShultzLD(January2017)."HumanizedMouseModelsofClinicalDisease".AnnualReviewofPathology.12(1):187–215.doi:10.1146/annurev-pathol-052016-100332.PMC 5280554.PMID 27959627. ^ItoR,TakahashiT,KatanoI,ItoM(May2012)."Currentadvancesinhumanizedmousemodels".Cellular&MolecularImmunology.9(3):208–14.doi:10.1038/cmi.2012.2.PMC 4012844.PMID 22327211. ^BosmaGC,CusterRP,BosmaMJ(February1983)."Aseverecombinedimmunodeficiencymutationinthemouse".Nature.301(5900):527–30.Bibcode:1983Natur.301..527B.doi:10.1038/301527a0.PMID 6823332.S2CID 4267981. ^abcdefYongKS,HerZ,ChenQ(August2018)."HumanizedMiceasUniqueToolsforHuman-SpecificStudies".ArchivumImmunologiaeetTherapiaeExperimentalis.66(4):245–266.doi:10.1007/s00005-018-0506-x.PMC 6061174.PMID 29411049. ^Tary-LehmannM,SaxonA,LehmannPV(November1995)."Thehumanimmunesysteminhu-PBL-SCIDmice".ImmunologyToday.16(11):529–33.doi:10.1016/0167-5699(95)80046-8.PMID 7495490. 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^BilityMT,ZhangL,WashburnML,CurtisTA,KovalevGI,SuL(September2012)."GenerationofahumanizedmousemodelwithbothhumanimmunesystemandlivercellstomodelhepatitisCvirusinfectionandliverimmunopathogenesis".NatureProtocols.7(9):1608–17.doi:10.1038/nprot.2012.083.PMC 3979325.PMID 22899330. ^WangLX,KangG,KumarP,LuW,LiY,ZhouY,et al.(February2014)."Humanized-BLTmousemodelofKaposi'ssarcoma-associatedherpesvirusinfection".ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmerica.111(8):3146–51.Bibcode:2014PNAS..111.3146W.doi:10.1073/pnas.1318175111.PMC 3939909.PMID 24516154. ^WegeAK,FlorianC,ErnstW,ZimaraN,SchleicherU,HansesF,et al.(2012-07-24)."Leishmaniamajorinfectioninhumanizedmiceinducessystemicinfectionandprovokesanonprotectivehumanimmuneresponse".PLOSNeglectedTropicalDiseases.6(7):e1741.doi:10.1371/journal.pntd.0001741.PMC 3404120.PMID 22848771.S2CID 7657105. 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^ZhengJ,WuWL,LiuY,XiangZ,LiuM,ChanKH,et al.(2015-08-18)."TheTherapeuticEffectofPamidronateonLethalAvianInfluenzaAH7N9VirusInfectedHumanizedMice".PLOSONE.10(8):e0135999.Bibcode:2015PLoSO..1035999Z.doi:10.1371/journal.pone.0135999.PMC 4540487.PMID 26285203.S2CID 10461525. ^abTianH,LyuY,YangYG,HuZ(2020)."HumanizedRodentModelsforCancerResearch".FrontiersinOncology.10:1696.doi:10.3389/fonc.2020.01696.ISSN 2234-943X.PMC 7518015.PMID 33042811.S2CID 221589508. ^HausserHJ,BrennerRE(July2005)."PhenotypicinstabilityofSaos-2cellsinlong-termculture".BiochemicalandBiophysicalResearchCommunications.333(1):216–22.doi:10.1016/j.bbrc.2005.05.097.PMID 15939397. ^WegeAK,SchmidtM,UeberhamE,PonnathM,OrtmannO,BrockhoffG,LehmannJ(2014-05-08)."Co-transplantationofhumanhematopoieticstemcellsandhumanbreastcancercellsinNSGmice:anovelapproachtogeneratetumorcellspecifichumanantibodies".mAbs.6(4):968–77.doi:10.4161/mabs.29111.PMC 4171030.PMID 24870377.S2CID 34234807. ^HerZ,YongKS,ParamasivamK,TanWW,ChanXY,TanSY,et al.(October2017)."Animprovedpre-clinicalpatient-derivedliquidxenograftmousemodelforacutemyeloidleukemia".JournalofHematology&Oncology.10(1):162.doi:10.1186/s13045-017-0532-x.PMC 5639594.PMID 28985760. ^HerZ,YongKS,ParamasivamK,TanWW,ChanXY,TanSY,et al.(October2017)."Animprovedpre-clinicalpatient-derivedliquidxenograftmousemodelforacutemyeloidleukemia".JournalofHematology&Oncology.10(1):162.doi:10.1186/s13045-017-0532-x.PMC 5639594.PMID 28985760.S2CID 25506701. ^ChenQ,WangJ,LiuWN,ZhaoY(July2019)."CancerImmunotherapiesandHumanizedMouseDrugTestingPlatforms".TranslationalOncology.12(7):987–995.doi:10.1016/j.tranon.2019.04.020.PMC 6529825.PMID 31121491. ^ZayoudM,ElMalkiK,FrauenknechtK,TrinschekB,KloosL,KarramK,et al.(September2013)."SubclinicalCNSinflammationasresponsetoamyelinantigeninhumanizedmice".JournalofNeuroimmunePharmacology.8(4):1037–47.doi:10.1007/s11481-013-9466-4.PMID 23640521.S2CID 503830. ^GunawanM,HerZ,LiuM,TanSY,ChanXY,TanWW,et al.(November2017)."ANovelHumanSystemicLupusErythematosusModelinHumanisedMice".ScientificReports.7(1):16642.Bibcode:2017NatSR...716642G.doi:10.1038/s41598-017-16999-7.PMC 5709358.PMID 29192160.S2CID 5604139. ^King,Marie;Pearson,Todd;Shultz,LeonardD.;Leif,Jean;Bottino,Rita;Trucco,Massimo;Atkinson,MarkA.;Wasserfall,Clive;Herold,KevanC.;Woodland,RobertT.;Schmidt,MadelynR.(2008-03-01)."AnewHu-PBLmodelforthestudyofhumanisletalloreactivitybasedonNOD-scidmicebearingatargetedmutationintheIL-2receptorgammachaingene".ClinicalImmunology.126(3):303–314.doi:10.1016/j.clim.2007.11.001.ISSN 1521-6616.PMID 18096436. Furtherreading[edit] BrehmMA,WilesMV,GreinerDL,ShultzLD(August2014)."Generationofimprovedhumanizedmousemodelsforhumaninfectiousdiseases".JournalofImmunologicalMethods.410:3–17.doi:10.1016/j.jim.2014.02.011.PMC 4155027.PMID 24607601. ItoR,TakahashiT,KatanoI,ItoM(May2012)."Currentadvancesinhumanizedmousemodels".Cellular&MolecularImmunology.9(3):208–14.doi:10.1038/cmi.2012.2.PMC 4012844.PMID 22327211. ScheerN,SnaithM,WolfCR,SeiblerJ(December2013)."Generationandutilityofgeneticallyhumanizedmousemodels".DrugDiscoveryToday.18(23–24):1200–11.doi:10.1016/j.drudis.2013.07.007.PMID 23872278. PeltzG(May2013)."Can'humanized'miceimprovedrugdevelopmentinthe21stcentury?".TrendsinPharmacologicalSciences.34(5):255–60.doi:10.1016/j.tips.2013.03.005.PMC 3682766.PMID 23602782. GrompeM,StromS(December2013)."Micewithhumanlivers".Gastroenterology.145(6):1209–14.doi:10.1053/j.gastro.2013.09.009.PMID 24042096. LeungC,ChijiokeO,GujerC,ChatterjeeB,AntsiferovaO,LandtwingV,et al.(September2013)."Infectiousdiseasesinhumanizedmice".EuropeanJournalofImmunology.43(9):2246–54.doi:10.1002/eji.201343815.PMID 23913412. Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Humanized_mouse&oldid=1069638574" Categories:ImmunologymiceHiddencategories:CS1:longvolumevalue Navigationmenu Personaltools NotloggedinTalkContributionsCreateaccountLogin Namespaces ArticleTalk English Views ReadEditViewhistory More Search Navigation MainpageContentsCurrenteventsRandomarticleAboutWikipediaContactusDonate Contribute HelpLearntoeditCommunityportalRecentchangesUploadfile Tools WhatlinkshereRelatedchangesUploadfileSpecialpagesPermanentlinkPageinformationCitethispageWikidataitem Print/export DownloadasPDFPrintableversion Languages العربيةFrançais日本語РусскийСрпски/srpski Editlinks