Immunodeficient Mice for Cancer Studies: Which host strain ...

Of the four scid strains mentioned above, NOD scid mice typically support higher levels of engraftment. However, NOD scid mice can develop ... 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Geneticsvs.genomics Ethicalconsiderations Personalizedmedicineandyou WhatisCRISPR? MiceinBiomedicalResearch AreasofResearch Addiction Aging Alzheimer's&OtherDementias Cancer Diabetes Microbiome Rarediseases Vision ClinicalKnowledgebase MaineCancerGenomicsInitiative News  JAXNews JAXBlog MinutetoUnderstanding Subscribe PressRoom TheSearchMagazine ExplorebyTopic AboutUs  FastFacts OurPeople&Culture OurValues Diversity,Equity&Inclusion FacesofJAX OurLeaders WorkWithUs OurCampuses&Communities OurImpact CollaborationatJAX OurMedicalImpact OurEconomicImpact OurCommunityImpact OurEnvironmentalImpact OurHistory Careers ContactUs Give JAXHome NewsandInsights JAXBlog BlogPost July08,2013 ImmunodeficientMiceforCancerStudies:WhichhoststrainshouldIuse? JimYeadon,Ph.D It’sastraightforwardquestionwithanot-so-straightforwardanswer! Fourclassesofimmunodeficientmice JAXdistributesavarietyofimmunodeficientstrainsthatcanbedividedintofourmaincategories: •“Nude”mice •“Scid”mice •“Rag-deficient”mice •“Higher-order,multigenic”immunodeficientmice AJAXNotesarticlethoroughlydescribestheseofferings.Briefly,“nude”micearehomozygousfortheFoxn1nu,or“nude,”mutation.Foxn1encodesatranscriptionfactorrequiredforbothhairfollicleandthymicdevelopment.Initsabsence,micearebothhairlessandathymic.Becausethethymusfailstoform,thereisnoplaceforCD4+andCD8+Tcellstodifferentiateandmature,makingnudehomozygotesTcell-deficient. “Scid”micearehomozygousforthePrkdcscidmutation.ThegenePrkdcencodesthecatalyticsubunitofDNA-dependentproteinkinasethatisrequiredforDNArepairandforsealingthedouble-strandedDNAbreaksthatoccurduringsomaticrecombinationofTcellreceptor(TCR)andimmunoglobulin(Ig)genes.IntheabsenceofPrkdcprotein,TCRandIggenescannotrearrange,resultinginmicethatarebothTandBcelldeficient. “Rag-deficient”micearemicethatfailtoexpressfunctionalRag1orRag2proteins.LikethePrkdcgene,bothRag1andRag2arerequiredforsomaticrecombinationofTCRandIggenes,andtheabsenceofeithergeneresultsinTandBcelldeficiency.MicethatcarryeithertheRag1tm1MomorRag2tm1.1Cgnmutationshaveverysimilar,ifnotidentical,phenotypes. Finally,“higher-order,multigenic”immunodeficientmiceareconstructedfromeitherPrkdcscidorRag-deficientmice,andcarryadditionalimmunodeficiency-enhancingmutations.AmongthesemiceareourNSGandNRGmice,whichcarryaspecificmutationintheinterleukin2receptorgammasubunitgene(Il2rgtm1Wjl)incombinationwiththePrkdcscidandRag1tm1Mom,respectively.ThesemiceareB,TandNKcelldeficient.Additionally,becausetheybothhaveNOD/ShiLtJgeneticbackgrounds,theyarehemolyticcomplement-deficientandcarryallelesthatadverselyaffectmacrophageanddendriticcellfunctions. Choosingatumorcellhost Choosingthebesthostforatumorstudyfromamongthesestrainsdependsonseveralfactors,including: Whattypeoftumordoyouwanttoengraft—e.g.,anestablishedcellline,ablood-bornetumor,oraslow-growingprimarytumor? Wherewillyouengraftthetumor—e.g.,subcutaneouslyororthotopically—andhowwillyouevaluateitsgrowth? Howlongdoyouneedthemicetoremainengrafted? MatchingyouranswerstothesequestionstothecharacteristicsofthemicedescribedintheComprehensiveImmunodeficientSuite shouldconsiderablynarrowyourhostchoices. Nudemice Ingeneral,nudemicemakeidealhostsforestablished,rapidlygrowingtumorcelllines.Becausetheyarehairless,theydon’thavetobeshavedordepilatedtoevaluatethegrowthofasubcutaneoustumor.Thehairlessphenotypealsomakesfollowingfluorescentlylabeledcellsbywhole-bodyimagingveryeasy.However,becausenudemicestillhaveBcellandrobustNKcellresponses,theyarenotsuitablehostsforblood-bornecancers,suchasleukemiasorlymphomas.Theyarealsopoorhostsforslow-growinghumanormouseprimarytumorcellsorheterogeneoustumorfragments. JAXmaintainslivecoloniesofthreedifferentnudestrains:NU/J(002019)inbredmice,B6-nude(000819)congenicmice,andJ:NU(007850)outbrednudes.Beinginbredandcongenic,respectively,NU/JandB6-nudesaregeneticallyhomogeneous.Therefore,theyarelikelytosupportmoreconsistenttumorgrowth.Incontrast,outbredJ:NUnudesmayexhibitmorevariabletumorgrowthbecausetheyaregeneticallyheterogeneous.Theiroutbrednature,however,makesthemmorevigorousthaneitherNU/JorB6-nudes,sotheymaybeabletowithstandmoreinvasiveorsevereexperimentalmanipulation.BecausebothNU/JandJ:NUmicearealbino,theymaybepreferredformonitoringtumorgrowthbywhole-bodyimaging. ScidandRag-deficientmice Ifyou’regoingtoengraftslow-growing,established,primarycelllines,orblood-bornecancers,scidandRag-deficientmicearebetterchoicesthannudemice.BothareTandBcell-deficientandthereforemoreimmunocompromisedthannudes.Tumorsthatgrowonlystubbornlyinnudemicelikelywillgrowmorerobustlyineitherofthesestrains. Ofthetwomodels,scidsareprobablymorewidelyusedastumorcellhosts,possiblybecausethey’vebeenaroundforalongtime–sincethe1990s–andarewidelyavailablefrommostmousevendors.However,theyareproneto“leakiness,”whichmeanstheymaydeveloplowlevelsofserumimmunoglobulins(Igs).SuchleakinessismorecommoninB6-(001913)andBALB/cscid(001803)mice,lesscommoninC3Hscid(001131)mice,andleastcommoninNOD-scid(001303)mice.Itisnotclearwhateffect,ifany,thisleakinesshasonthesuitabilityofthesemiceastumorcellhosts.Studiesindicatethattherepertoireofantigensthatthe“leaky”Igsrecognizeissmall,anddatalinkingleakinesstotissuerejectionorpoortumorgrowthisweak. Ofthefourscidstrainsmentionedabove,NODscidmicetypicallysupporthigherlevelsofengraftment.However,NODscidmicecandevelopthymiclymphomas,whichlimittheiraveragelifespantoapproximately30weeks.Therefore,NODscidmicemaynotbesuitablehostsforlong-termengraftmentstudies. BecausePrkdcproteinisinvolvedinDNArepair,scidmutantsareradiation-sensitiveandthereforemaynotbesuitablehostsiftheyneedtobeirradiated.Ontheotherhand,becausetheRagproteinsarenotinvolvedinDNArepair,Rag-deficientmiceareradiation-resistant.Moreover,theyarenot“leaky.”Indeed,Rag-deficientmicehaveoccasionallybeenreferredtoas“non-leakyscids.” BecauseneitherscidnorRag-deficientmicearehairless,theyneedtobeshavedordepilatedtomonitorthegrowthofasubcutaneoustumor. Higher-orderimmunodeficientmice:Preferredhostsforhumanprimarytumors Ifyou’regoingtoengrafthumanandmouseprimarytumors,you’llprobablyneedagreaterdegreeofimmunodeficiencythanthatprovidedbynude,scid,orRag-deficientmice.Overtheyears,severalstrainshavebeenproducedthatcombineadditionalmutationswitheitherscidorRagdeficiencytofurthersuppressamouse’simmuneresponses.Theseincludescidbeige(Lystbg),NODscid/(b2-microglobulin(B2m)-deficient(002570),andNODRag1/perforin1(Prf1)-null(004848)mice.Morerecently,NSGandNRGmice,whichcombinethescidandRag1mutationsrespectivelywithadeficiencyintheinterleukin2receptorgammachain(Il2rg),havebeendevelopedthatsupportmorerobustpost-engraftmenttumorgrowththattheearlier,double-mutantmice.Moreover,humanprimarytumorsengraftedintoNSGmiceretainmoreoftheirnativecytostructuralandstromalcharacteristicsthanwhentheyareengraftedintoBALB/cscidmice.TheunparalleledimmunedeficiencyofNSGmicehasmadethemapreferredhostforestablishingandpassagingthehumanprimarytumorsinourPatient-DerivedXenograft(PDX)Resource,whichnowcontainsmorethan200established,low-passagemodels. TheonlymajordisadvantagewhenusingNSGorNRGastumorhostsisthatthemicedohavehairandmustbeshavedordepilatedtomonitorthegrowthofsubcutaneoustumors.Further,inatleastonestudy,NSGmiceweretoopermissive:melanomacellsthatnormallyarenottumorigenicinahumanpatientformedtumorsinthismouse.Inthatstudy,NODscidhostswerefoundtomorefaithfullyrecapitulatethemalignanciesnormallyobservedinhumancancerpatients. Ingeneral,themoreseverelyimmunocompromisedamousehost,themorelikelyitisthattumorcelllineorprimarytumorwillgrow.Inmanycases,however,alessimmunocompromisedhostwillsupportadequatetumorgrowth.Thechoiceofanimmunodeficienthost,then,dependsgreatlyontheoriginofthetumorigeniccellsandtheirtypicalgrowratewhentransplantedintoahost.Foradditionalguidanceinchoosinganimmunodeficienthostforanysortoftumorengraftmentstudy,pleasecontactourTechnicalInformationServicesgroup. Topics Immunodeficiency Cancer/Tumors ModelDevelopment GeneticsandGenomics ResourceDevelopmentandDissemination ImmuneDisorders Cancer BlogPost December09,2021 StudyingCRSinaDiversePopulation AutoimmuneDiseasesInformation BlogPost November23,2021 Navigatingprecisionmedicineincancer BlogPost October25,2021 Assessingpatienthealthriskswithlimitedorunknownfamilyhistory Precisionmedicine BlogPost September01,2021 Underrepresented,underservedandunderstudied BreastCancer YouMayAlsoBeInterestedin Nov 09-11 Workshop WorkshoponVascularCatheterizationintheLaboratoryMouse ModelDevelopment, GeneticTools Aug 14-26 ShortCourse 31stAnnualShortCourseonExperimentalModelsofHumanCancer Sep 26-30 Workshop 20thAnnualWorkshoponthePathologyofMouseModelsforHumanDisease ModelDevelopment, Stemcells, Aging, AutoimmuneDiseasesInformation, BonesandJoints, Dermatology, Cancer/Tumors, Digestion Jul 18-28 ShortCourse HumanandMammalianGeneticsandGenomics:The63rdMcKusickShortCourse Precisionmedicine, Ethics, Stemcells, Microbiome, InfectiousDisease, ImmunologyInflammationandRheumatology, ModelDevelopment, RareDiseases, Aging, Cardiovascular, Cancer/Tumors, DevelopmentalBiology, Diabetes, GeneticTools, OptogeneticsandPharmacogenetics, Autoimmunity, Inflammation, Lupus, Addiction, Dermatology, AutoimmuneDiseasesInformation, MetabolicDiseases, NeurodegenerativeDisease, ReproductiveBiology, DownSyndrome, FragileX, RettSyndrome, BreastCancer, NeurodevelopmentalDefects, MetabolicDefects, CysticFibrosis Sep 05-10 Workshop TechniquesinModelingHumanCancerinMice Endocrinology, GeneticTools, RareDiseases, NeurodegenerativeDisease, Cancer/Tumors Jun 27-30 Workshop WorkshoponSurgicalTechniquesintheLaboratoryMouse(inParis,France) ModelDevelopment, GeneticTools Oct 10-13 ShortCourse TheShortCourseontheApplicationofMachineLearningforAutomatedQuantificationofBehavior LungsRespiratory, ModelDevelopment Oct 03-06 Workshop ColonyManagement&Biomethods