Scid mutants or Rag2 Knockouts - Which Immunodeficient ...

The NOD scid is special in that the NOD inbred strain background imparts some additional immunodeficiency. NOD mice lack complement C5, and they ... FindYourModel FindYourModel ModelSearch GEMs TaconicTransgenicModels™EmergingModelsCryopreservedModels StandardStrainsandStocks InbredOutbredHybrid/Congenic StandardImmunodeficients DietInducedMice HumanizedImmuneSystemMice huNOG-EXLModelPortfolioNOGPortfolio TherapeuticAreas&Solutions IBDPortfolioMicrobiomePortfolioNeurosciencePortfolioOncologyImmuno-OncologytADMET™Portfolio 2022PricingGuide DesignYourModel DesignYourModel DesignYourModel KnockoutMice Knock-inModels TransgenicMice KnockdownMice CRISPRGeneEditing ExpressMODEL®:EmbryonicStemCell ExpressMODEL®:RandomIntegrationTransgenic DrugDevelopment ModelGenerationSolutionsPublications MilestoneReports InquiryForm Taconic-CyagenAlliance BreedYourModel BreedYourModel ColonyManagement AnimalBreedingandHusbandry AnimalModelHousingHealthMonitoringBreedingServicesBackcrossingandSpeedCongenics RederivationandRapidEXPANSION™ MouseandRatRederivationRapidEXPANSION™ CryopreservationandCryorecovery SpermandEmbryoCryopreservationCryorecoveryandFRapid®Expansion ProjectManagement ProjectManagementTeameTACONIC®Platform GenotypingandGeneticAnalysis GenotypingServicesTransgeneCharacterizationGeneExpressionAnalysisGeneticProfiling(SNPTesting) ColonyManagementPublications PrepareYourModel PrepareYourModel PrepareYourModel MicrobiomeSolutionsandGerm-FreeMice Germ-FreeMiceGerm-FreeDerivationsTruBIOME®FecalMicrobiotaTransplantationServiceFecalPelletsandMicrofloraDonorsMicrobiomeResources PreconditioningSolutions SpecialDietAdministrationAnimalAgingSurgicalModelsandServicesRodentID MurineBiospecimenCollection AnimalShippingProducts Contact searchsite searchsite eTACONIC FindYourModel ModelSearch GEMs TaconicTransgenicModels™EmergingModelsCryopreservedModels StandardStrainsandStocks InbredOutbredHybrid/Congenic StandardImmunodeficients DietInducedMice HumanizedImmuneSystemMice huNOG-EXLModelPortfolioNOGPortfolio TherapeuticAreas&Solutions IBDPortfolioMicrobiomePortfolioNeurosciencePortfolioOncologyImmuno-OncologytADMET™Portfolio 2022PricingGuide DesignYourModel DesignYourModel KnockoutMice Knock-inModels TransgenicMice KnockdownMice CRISPRGeneEditing ExpressMODEL®:EmbryonicStemCell ExpressMODEL®:RandomIntegrationTransgenic DrugDevelopment ModelGenerationSolutionsPublications MilestoneReports InquiryForm Taconic-CyagenAlliance BreedYourModel ColonyManagement AnimalBreedingandHusbandry AnimalModelHousingHealthMonitoringBreedingServicesBackcrossingandSpeedCongenics RederivationandRapidEXPANSION™ MouseandRatRederivationRapidEXPANSION™ CryopreservationandCryorecovery SpermandEmbryoCryopreservationCryorecoveryandFRapid®Expansion ProjectManagement ProjectManagementTeameTACONIC®Platform GenotypingandGeneticAnalysis GenotypingServicesTransgeneCharacterizationGeneExpressionAnalysisGeneticProfiling(SNPTesting) ColonyManagementPublications PrepareYourModel PrepareYourModel MicrobiomeSolutionsandGerm-FreeMice Germ-FreeMiceGerm-FreeDerivationsTruBIOME®FecalMicrobiotaTransplantationServiceFecalPelletsandMicrofloraDonorsMicrobiomeResources PreconditioningSolutions SpecialDietAdministrationAnimalAgingSurgicalModelsandServicesRodentID MurineBiospecimenCollection AnimalShippingProducts Contact searchsite searchsite eTACONIC Taconic TaconicInsightsImmunologyScidmutantsorRag2knockouts MeganM.MacBride,PhDThursday,December17,2015 Facebook  Twitter  Linkedin  print  rss Micewithcompromisedimmunesystemsareinvaluableresearchtools.Startingwiththediscoveryofathymicnudemiceinthe1960's,theportfolioofimmunodeficientrodentshasgrownsignificantly.Althoughthesemodelsareusedquitewidely,notallresearchersunderstandtheirintrinsiccharacteristicsandhowthosecharacteristicsimpactexperimentaloutcomes.Learnmoreabouttwokeyimmunodeficientmodels,scidmutantsandRag2knockouts,andhowtochoosethemostappropriatemodelforyourstudy. ThescidMutation Thescidmutationwasfirstdiscoveredin1983byMelBosmaattheFoxChaseCancerCenter1.Scidstandsforseverecombinedimmunodeficiency.ThismutationarosespontaneouslyinacolonyofC.B-17micethatBosmawasusingforstudiesofimmunoglobulinisotypes.ThescidmutationisamutationinthePrkdcgene,proteinkinase,DNAactivated,catalyticpolypeptide.ThespecificgeneticalterationinthePrkdcscidalleleisanT-to-Atransversionpointmutationatcodon4095,whichcreatesaprematurestopcodon2,3.PrkdcisinvolvedinDNArepairvianon-homologousendjoining(NHEJ).V(D)Jrecombination,whichrearrangesthegeneticcomponentsofantibodiesandTcellreceptorsduringBandTcelldevelopment,requiresNHEJforproperfunction. DuetotheNHEJdefectinPrkdcscidmutants,scidmicelackbothmatureTandBcells.Asoneofthefirstimmunodeficientmodelsavailable,thatoriginalscid,theC.B-17scid,wasdisseminatedworldwideandhasbeenusedinthousandsofstudies.ThePrkdcscidallelewasalsobackcrossedontootherstrainandstockbackgroundstomakemodelssuchastheoutbredICRscidandtheNODscid.AmongthescidsthatTaconicBiosciencesoffers,theC.B-17scidisthemostrequested,primarilyduetothewealthofhistoricaldataandpublicationsusingthestrain.Butitmaynotalwaysbethebestexperimentalchoice. DevelopmentofsomefunctionalTandBcells Scidmicecanbecome"leaky",meaningthatsomefunctionalTandBcellscandevelop.ThisappearstoarisefromalowfrequencyofV(D)Jcodingjointformation,withrecombinationoftenoccurringatsectionsofshorthomology5.Thisleakinessvariesbythestrain/stockbackground,withageandbyhousingconditions,withtheoriginalC.B-17scidactuallybeingtheleakieststrain. IgG+MantibodylevelsintheserafromagedNOG(7-10monthsold)andNOD-scid(6-7monthsold)miceweremeasuredbyELISA.InC.B-17-scid(6-9monthsold)mice,serumIgG+M+Aantibodylevelsmeasuredin1989wereusedinthisfigure. WhiletheC.B-17scidmaybefineforshorttermexperiments,longertermexperimentsmaybechallenging.TheICRscidisalessleakyalternativeonanoutbredbackground.Asanoutbred,ICRscidmicearelarger,hardierandlessexpensive.However,theoutbredbackgroundcanintroducemoreexperimentalvariation.Notethatlargeranimalsalsorequireadditionalcompoundfordosing.Ingeneral,theICRscidisanexcellentvalue.TheNODscidisspecialinthattheNODinbredstrainbackgroundimpartssomeadditionalimmunodeficiency.NODmicelackcomplementC5,andtheyhavedefectsinmacrophageanddendriticcellfunction.Theyarealsoonthelessleakyendofthespectrum.Thismakesitthemostimmunocompromisedofthebasicscidmodels.ThemajordrawbacktotheNODscidisthatitdevelopsthymiclymphomasatahighrate,sotheeffectivelifespanissomewherebetween7-9months.LongertermstudiesarenotadvisableintheNODscidstrain. Thescidmutationintroducesafewotherspecialconsiderations.AsthismutationaffectsDNArepair,micecarryingPrkdcscidaremoresensitivetoradiation.Theyarethusnotidealchoicesforexperimentsinvolvingclinicallyrelevantradiationdoses.ScidmicemayalsobemoresensitivetodrugswhichdamageDNA.Whenusingdrugswiththistypeofmechanism,atolerancestudyisrecommendedtohelpchooseappropriatedosesforfollowonefficacystudies. KnockoutoftheRag2geneThebasicmechanismofV(D)Jrecombination.AdaptedfromNatureReviewsGenetics. Rag2knockoutsaresomewhatlesserknowncomparedtoscidmicebutoffernumerousadvantages.TheRag2gene,recombinationactivatinggene2,wasknockedoutin1992byFrederickAltatColumbiaUniversity6.TheRag2proteinisalsoinvolvedinV(D)Jrecombination.BothRag2andRag1bindDNAatrecombinationsignalsequencesandcreatesinglestrandnicksasthefirststepofrecombination.ArrestingthispathwayblocksmaturationofTandBcells4.SotheimmunodeficientphenotypeofRag2knockoutsissimilartothatofscidmice.OnebigdifferenceisthattheRag2mutationisnotleaky.KnockingoutRag1orRag2meansthatV(D)Jrecombinationcannotbeinitiated,sonoleakinessoccursthroughdownstreamsuccessfulrecombinationeventsasinthescid.Thenon-leakyphenotypeofRag2knockoutmiceallowslongertermexperimentswithoutworryofincreasedgraftrejectionasthemiceage.Rag2micealsotoleratehigherradiationdosescomparedtoscidmice.TheRag2mutationhasbeenbackcrossedtoanumberofbackgrounds,primarilyinbredstrains,aswellascombinedwithothermutationstomakeanumberofusefulmodelsbothforoncologyasxenografthostsaswellasinbasicimmunologyresearch.Rag2knockoutmodelstendtobeusedquitewidelyinadoptivetransferexperiments,bothduetotheavailabilityonkeystrainbackgroundssuchasB6andBALB/caswellastotheirnon-leakynature. Sowhyisn'ttheRag2usedaswidelyasthescid?Muchofthiscanbetracedtohistoricalaccidentandtheweightofthepublicationrecord.Thescidgotaheadstart!ButresearchersarestartingtorealizetheadvantagesoftheRag2knockoutandchooseitforexperimentswhereascidmighthavedrawbacks.UseofRag2knockoutshasincreasedsignificantly,andthattrendislikelytocontinue.Foryournextexperiment,considercarefullytheuniquecharacteristicsofthesetwomodelsanddeterminewhichbestmeetsyourneeds. Areyouplanninganexperimentwithimmunocompromisedmice?TakeadvantageofourSmartSelectProgram.SmartSelectisacomplimentaryanimalmodeltrialprogramallowingyoutotrialupto20animalsinyourfacilityatnocosttoyourorganization.Learnmoretoday.References:1.BosmaGC,CusterRP,BosmaMJ.(1983)Aseverecombinedimmunodeficiencymutationinthemouse.Nature.301(5900):527-30.2.BluntT,GellD,FoxM,TaccioliGE,LehmannAR,JacksonSP,JeggoPA.(1996)Identificationofanonsensemutationinthecarboxyl-terminalregionofDNA-dependentproteinkinasecatalyticsubunitinthescidmouse.ProcNatlAcadSciUSA.93(19):10285-90.3.ArakiR,FujimoriA,HamataniK,MitaK,SaitoT,MoriM,FukumuraR,MorimyoM,MutoM,ItohM,TatsumiK,AbeM.(1997)NonsensemutationatTyr-4046intheDNA-dependentproteinkinasecatalyticsubunitofseverecombinedimmunedeficiencymice.ProcNatlAcadSciUSA.94(6):2438-43.4.LieberMR.(2010)Themechanismofdouble-strandDNAbreakrepairbythenonhomologousDNAend-joiningpathway.AnnuRevBiochem.79:181-211.5.KotloffDB,BosmaMJ,RuetschNR.(1993)V(D)JrecombinationinperitonealBcellsofleakyscidmice.JExpMed.178(6):1981-94.6.ShinkaiY,RathbunG,LamKP,OltzEM,StewartV,MendelsohnM,CharronJ,DattaM,YoungF,StallAM,etal.(1992)RAG-2-deficientmicelackmaturelymphocytesowingtoinabilitytoinitiateV(D)Jrearrangement.Cell.68(5):855-67. ←InsightsfromthehuNOGproductionLab-ProductintegrityReview:HumanizedMouseModelResearchSymposia→ TaconicInsights ADMET Alzheimer'sDisease AnimalWelfare CardiovascularDisease ColonyManagementSolutions Cryopreservation Genetics Immunology InfectiousDisease Inflammation MetabolicDisease MicrobiomeandGerm-Free ModelGenerationSolutions Neuroscience OncologyandImmuno-Oncology Parkinson'sDisease Quality TACONICINSIGHTS SUBSCRIBE NevermissanInsight! MostPopularInImmunologyScidmutantsorRag2Knockouts-WhichImmunodeficientModelisBestforYourStudy? ConfusedAboutLy5,Cd45,andPtprc? AutoimmunityinHumanizedImmuneSystemMice:ADouble-edgedSword ComparisonGuide:huNOG-EXL,NSG-SGM3andMISTRG Close Welcome!Tellusalittleaboutyourself Hereweshowthechatwindow.