2024
Single-cell transcriptomics of CD8 T cells in autoimmune diabetes after anti-CD3 monoclonal antibody treatment
Wu Y, Spurrell M, Deng S, Herold K. Single-cell transcriptomics of CD8 T cells in autoimmune diabetes after anti-CD3 monoclonal antibody treatment. The Journal Of Immunology 2024, 212: 0998_4625-0998_4625. DOI: 10.4049/jimmunol.212.supp.0998.4625.Peer-Reviewed Original ResearchPancreas-draining lymph nodesIslet-infiltrating CD8 T cellsCD8 T cellsPre-diabetic NODAnti-CD3 mAbDiverse TCR repertoireT cellsNOD miceTCR repertoireTCF-1Pre-diabetic NOD miceImmune mediated destructionDiabetic NOD miceMonoclonal antibody treatmentLong-term toleranceExpression of EomesExpression of TCF-1Expression of TOXFragments of mAbsDelay type 1 diabetesType 1 diabetesAnti-CD3Autoimmune diabetesAntibody treatmentLymph nodes
2022
RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice.
Joshi AA, Wu Y, Deng S, Preston-Hurlburt P, Forbes JM, Herold KC. RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice. Clinical Immunology 2022, 245: 109165. PMID: 36257528, DOI: 10.1016/j.clim.2022.109165.Peer-Reviewed Original ResearchConceptsXenograft rejectionIL-17AHumanized miceIL-1βT cellsImmune responseRAGE antagonistsAdaptive human immune responsesPD-1 expressionSkin graft rejectionHuman immune cell responsesImmune cell responsesHuman immune responseHuman immune cellsInnate immune responseAdvanced glycation endproductsInhibition of pathwaysSmall molecule antagonistsMultiple inflammatory processesAZ therapyRAGE antagonismGraft rejectionIL-23Serum levelsMedian timeImmune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes
Perdigoto AL, Deng S, Du KC, Kuchroo M, Burkhardt DB, Tong A, Israel G, Robert ME, Weisberg SP, Kirkiles-Smith N, Stamatouli AM, Kluger HM, Quandt Z, Young A, Yang ML, Mamula MJ, Pober JS, Anderson MS, Krishnaswamy S, Herold KC. Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes. JCI Insight 2022, 7: e156330. PMID: 35925682, PMCID: PMC9536276, DOI: 10.1172/jci.insight.156330.Peer-Reviewed Original ResearchConceptsCheckpoint inhibitorsΒ-cellsPD-1/PD-L1 pathwayT-lymphocyte antigen-4PD-1 blockadePD-L1 pathwayDeath ligand 1NOD mouse modelDevelopment of diabetesHuman β-cellsAutoimmune complicationsNOD miceΒ-cell populationDeath-1Diabetes mellitusImmune infiltratesInflammatory mediatorsPancreatic inflammationPD-L1Induced diabetesLymphocytic infiltrationInflammatory cytokinesAntigen-4Immune cellsT cells
2021
Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
Rui J, Deng S, Perdigoto AL, Ponath G, Kursawe R, Lawlor N, Sumida T, Levine-Ritterman M, Stitzel ML, Pitt D, Lu J, Herold KC. Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes. Nature Communications 2021, 12: 5074. PMID: 34417463, PMCID: PMC8379260, DOI: 10.1038/s41467-021-25367-z.Peer-Reviewed Original ResearchConceptsImmune cellsΒ-cellsNOD/SCID recipientsDiabetogenic immune cellsDiabetogenic T cellsBone marrow transplantType 1 diabetesExpression of TET2Human β-cellsIslet infiltratesSCID recipientsMarrow transplantInflammatory pathwaysTransfer of diseaseT cellsInflammatory genesImmune killingPathologic interactionsReduced expressionDiabetesInflammationTET2MiceRecipientsCells
2020
Use of CART cells to selectively target autoantigen-specific T cells for the treatment of autoimmune diabetes
Yu H, Bettini M, Ellis G, Riley J, Collins J, Preston-Hurlburt P, Korah M, Mallone R, Deng S, Wang X, Fremont D, Spiegel D, Cresswell P, Herold K. Use of CART cells to selectively target autoantigen-specific T cells for the treatment of autoimmune diabetes. The Journal Of Immunology 2020, 204: 238.8-238.8. DOI: 10.4049/jimmunol.204.supp.238.8.Peer-Reviewed Original ResearchCART cellsT cellsAutoimmune diabetesCAR constructsHuman antigen-specific CD8Autoantigen-specific T cellsAntigen-specific CD8Pathogenic T cellsPrevious clinical trialsΒ-cell damageChimeric antigen receptorNon-specific actionT cell linesHuman T cellsDominant cell typeHuman insulitisPathogenic subpopulationsNovel immunotherapiesPrimary human T cellsClinical trialsPrimary mediatorPeptide epitopesAntigen receptorMicroglobulin complexCAR signaling
2017
Microbiota control immune regulation in humanized mice
Gülden E, Vudattu NK, Deng S, Preston-Hurlburt P, Mamula M, Reed JC, Mohandas S, Herold BC, Torres R, Vieira SM, Lim B, Herazo-Maya JD, Kriegel M, Goodman AL, Cotsapas C, Herold KC. Microbiota control immune regulation in humanized mice. JCI Insight 2017, 2: e91709. PMID: 29093268, PMCID: PMC5752290, DOI: 10.1172/jci.insight.91709.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsAntibodies, AntinuclearAntibodies, Monoclonal, HumanizedAutoimmune DiseasesB7-2 AntigenCD11b AntigenCD11c AntigenCD3 ComplexCD8-Positive T-LymphocytesCytokinesDisease Models, AnimalGastrointestinal MicrobiomeGastrointestinal TractGraft RejectionHumansImmunosuppressive AgentsImmunotherapyInterferon-gammaInterleukin-10Interleukin-27Leukocytes, MononuclearMiceMice, KnockoutMucous MembraneSkin TransplantationSTAT5 Transcription FactorT-LymphocytesTransplantation, HeterologousConceptsT cellsIL-10Humanized miceHuman peripheral blood mononuclear cellsPeripheral blood mononuclear cellsIL-27 expressionIL-10 levelsAnti-nuclear antibodiesEffector T cellsLevels of IFNCentral memory cellsLess IL-10Markers of efficacyBlood mononuclear cellsExpression of CD86Immune regulatory pathwaysIL-10 inductionHuman immune cellsHuman stool samplesImmunosuppressive medicationsIL-27Xenograft rejectionImmune therapyMononuclear cellsAntibiotic treatmentOral treatment with foralumab, a fully human anti-CD3 monoclonal antibody, prevents skin xenograft rejection in humanized mice
Ogura M, Deng S, Preston-Hurlburt P, Ogura H, Shailubhai K, Kuhn C, Weiner HL, Herold KC. Oral treatment with foralumab, a fully human anti-CD3 monoclonal antibody, prevents skin xenograft rejection in humanized mice. Clinical Immunology 2017, 183: 240-246. PMID: 28739191, DOI: 10.1016/j.clim.2017.07.005.Peer-Reviewed Original ResearchConceptsSkin xenograft rejectionOral treatmentXenograft rejectionT cellsAnti-CD3 monoclonal antibodyConsecutive daily dosesPeripheral T cellsActivation of splenocytesHuman immune systemSplenic CD8Graft acceptanceWeekly dosingIL-10Serum levelsImmune therapySmall bowelHumanized miceDaily dosesImmune modulationMucosal barrierIntragastric doseOral administrationSkin graftsProliferative responseLymphoid cellsβ Cells that Resist Immunological Attack Develop during Progression of Autoimmune Diabetes in NOD Mice
Rui J, Deng S, Arazi A, Perdigoto AL, Liu Z, Herold KC. β Cells that Resist Immunological Attack Develop during Progression of Autoimmune Diabetes in NOD Mice. Cell Metabolism 2017, 25: 727-738. PMID: 28190773, PMCID: PMC5342930, DOI: 10.1016/j.cmet.2017.01.005.Peer-Reviewed Original ResearchConceptsΒ-cellsImmune attackNon-obese diabetic (NOD) miceImmune inhibitory markersProgression of T1DChronic autoimmune diseaseType 1 diabetesLong-term survivalNormal β-cellsHuman β-cellsIslet infiltratesAutoimmune diabetesNOD miceDiabetic miceAutoimmune diseasesInhibitory markersImmune cellsImmune responseDiabetesStemness genesΒ cell identity genesSimilar changesCell deathDiseaseMice
2016
Characterization of Diabetogenic CD8+ T Cells IMMUNE THERAPY WITH METABOLIC BLOCKADE*
Garyu JW, Uduman M, Stewart A, Rui J, Deng S, Shenson J, Staron MM, Kaech SM, Kleinstein SH, Herold KC. Characterization of Diabetogenic CD8+ T Cells IMMUNE THERAPY WITH METABOLIC BLOCKADE*. Journal Of Biological Chemistry 2016, 291: 11230-11240. PMID: 26994137, PMCID: PMC4900270, DOI: 10.1074/jbc.m115.713362.Peer-Reviewed Original ResearchConceptsPrediabetic NOD miceNOD miceT cellsDiabetogenic CD8Reactive cellsMemory precursor effector cellsType 1 diabetes mellitusΒ-cellsGlucose tolerance deterioratesAutoreactive T cellsHyperglycemic NOD miceInsulin-producing β-cellsAutoimmune effectorsAutoimmune diabetesReactive CD8Glucose intoleranceDiabetes mellitusEffector cellsImmune therapyMetabolic disturbancesTolerance deterioratesDisease progressionInsulin pelletsSubset of cellsConventional antigensMethylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice
Rui J, Deng S, Lebastchi J, Clark PL, Usmani-Brown S, Herold KC. Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice. Diabetologia 2016, 59: 1021-1029. PMID: 26910463, PMCID: PMC4826795, DOI: 10.1007/s00125-016-3897-4.Peer-Reviewed Original ResearchConceptsInsulin gene expressionGene expressionQuantitative real-time RT-PCRMethylation marksInsulin geneNOD miceBeta cellsDNA methyltransferasesDisease progressionAims/hypothesisType 1 diabetesIns2 geneInsulin DNAMethylationReal-time RT-PCRGenesBeta-cell functionExon 1Human beta cellsBeta-cell massPancreatic beta cellsType 1 diabetesMethyltransferasesEffects of cytokinesExon 2Cell mass
2015
A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice
Gill RG, Pagni PP, Kupfer T, Wasserfall CH, Deng S, Posgai A, Manenkova Y, Hani A, Straub L, Bernstein P, Atkinson MA, Herold KC, von Herrath M, Staeva T, Ehlers MR, Nepom GT. A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice. Diabetes 2015, 65: 1310-1316. PMID: 26718498, PMCID: PMC5860426, DOI: 10.2337/db15-0492.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalAutoimmune DiseasesBiomedical ResearchCD3 ComplexDiabetes Mellitus, Type 1Drug Administration ScheduleDrug Therapy, CombinationFemaleImmunoglobulin Fab FragmentsImmunotherapyInsulinInsulin SecretionInsulin-Secreting CellsInterleukin-1 Receptor Accessory ProteinInterleukin-1betaMice, Inbred NODMulticenter Studies as TopicPilot ProjectsReceptors, Interleukin-1 Type IRecombinant Fusion ProteinsReproducibility of ResultsResearch DesignSpecific Pathogen-Free OrganismsUnited StatesConceptsNew-onset diseaseIL-1 blockadeAnti-CD3 treatmentNOD micePreclinical studiesInterleukin-1IL-1β monoclonal antibodyIslet β-cell massNOD mouse modelImmune Tolerance NetworkType 1 diabetesΒ-cell massApplicable immunotherapiesFuture clinical useStudy entryProspective studyClinical trialsMouse modelMulticenter consortiumAnimal modelsCandidate therapeuticsClinical useTherapeutic agentsMonoclonal antibodiesDiseaseSodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells
Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, Hafler DA. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. Journal Of Clinical Investigation 2015, 125: 4212-4222. PMID: 26524592, PMCID: PMC4639983, DOI: 10.1172/jci81151.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntibodies, NeutralizingAutoimmunityCD4-Positive T-LymphocytesCells, CulturedCoculture TechniquesColitisCytokinesForkhead Transcription FactorsGene Expression ProfilingGenes, ReporterGraft vs Host DiseaseHeterograftsHumansImmediate-Early ProteinsInflammationInterferon-gammaLeukocytes, MononuclearMaleMiceProtein Serine-Threonine KinasesRNA InterferenceRNA, Small InterferingSodium ChlorideSodium Chloride, DietaryT-Lymphocytes, RegulatoryConceptsHigh-salt dietTreg functionIFNγ secretionCD4 effector cellsHuman Treg functionRegulatory T cellsAdoptive transfer modelAnti-IFNγ antibodyHost disease modelType 1 diabetesInduction of proinflammatoryTreg pathwayExperimental colitisXenogeneic graftEffector cellsMultiple sclerosisProinflammatory responseT cellsTregsMurine modelSuppressive activitySuppressive functionSerum/glucocorticoid-regulated kinaseAutoimmunityGlucocorticoid-regulated kinase
2014
CD45 ligation expands Tregs by promoting interactions with DCs
Camirand G, Wang Y, Lu Y, Wan YY, Lin Y, Deng S, Guz G, Perkins DL, Finn PW, Farber DL, Flavell RA, Shlomchik WD, Lakkis FG, Rudd CE, Rothstein DM. CD45 ligation expands Tregs by promoting interactions with DCs. Journal Of Clinical Investigation 2014, 124: 4603-4613. PMID: 25202978, PMCID: PMC4191025, DOI: 10.1172/jci74087.Peer-Reviewed Original ResearchConceptsT cellsTreg proliferationTreg expansionVivo expansionRegulatory T cellsConventional T cellsTransfer of TregsActivated T cellsTreg numbersTreg populationImmune toleranceHomeostatic proliferationWT miceExogenous antigensPeripheral homeostasisTregsImmune responseTherapeutic useCD45 ligationNuclear factorIntegrin-dependent mannerNuclear translocationLigationAntigenProliferationHumanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy
Vudattu NK, Waldron-Lynch F, Truman LA, Deng S, Preston-Hurlburt P, Torres R, Raycroft MT, Mamula MJ, Herold KC. Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy. The Journal Of Immunology 2014, 193: 587-596. PMID: 24943216, PMCID: PMC4123131, DOI: 10.4049/jimmunol.1302455.Peer-Reviewed Original ResearchMeSH KeywordsAdrenal GlandsAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAutoimmune DiseasesCytokinesDisease Models, AnimalFlow CytometryHumansInterleukin Receptor Common gamma SubunitIpilimumabLiverLymphocyte ActivationMacrophagesMiceMice, Inbred NODMice, KnockoutMice, SCIDPhosphorylationSTAT5 Transcription FactorStem Cell TransplantationSurvival AnalysisT-LymphocytesT-Lymphocytes, RegulatoryTransplantation, HeterologousWeight LossConceptsAnti-nuclear AbsAutoimmune diseasesRegulatory cellsHumanized miceT cellsImmune responseWeight lossMesenteric lymph nodesHuman autoimmune diseasesInduction of autoimmunityT-cell immunotherapyRelease of IFNHuman immune responseImmune-deficient miceIpilimumab treatmentInflammatory sequelaeLymph nodesCell immunotherapyIP-10Macrophage infiltrationCytokine productionSpleen cellsPathologic processesHepatitisMice
2013
Transplant Tolerance to Pancreatic Islets Is Initiated in the Graft and Sustained in the Spleen
Gagliani N, Jofra T, Valle A, Stabilini A, Morsiani C, Gregori S, Deng S, Rothstein DM, Atkinson M, Kamanaka M, Flavell RA, Roncarolo MG, Battaglia M. Transplant Tolerance to Pancreatic Islets Is Initiated in the Graft and Sustained in the Spleen. American Journal Of Transplantation 2013, 13: 1963-1975. PMID: 23834659, PMCID: PMC3869180, DOI: 10.1111/ajt.12333.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntibodies, MonoclonalCD4 AntigensCD4-Positive T-LymphocytesForkhead Transcription FactorsGraft SurvivalIslets of LangerhansIslets of Langerhans TransplantationLeukocyte Common AntigensMiceMice, Inbred BALB CMice, Inbred C57BLSpleenT-Lymphocytes, RegulatoryTransplantation ToleranceTransplantation, HomologousConceptsTr1 cellsLong-term toleranceTransplant toleranceRegulatory type 1 (Tr1) cellsSpecific immunomodulatory treatmentTreg cell transferCD25- T cellsRegulatory cell typesType 1 cellsAllograft toleranceImmunomodulatory treatmentTreg cellsAllogeneic transplantationT cellsMouse modelImmune systemTregsPancreatic isletsSpleenAllograftsCell typesCellsRegulatory functionsTransplantationEngraftmentImmune Therapy and β-Cell Death in Type 1 Diabetes
Lebastchi J, Deng S, Lebastchi AH, Beshar I, Gitelman S, Willi S, Gottlieb P, Akirav EM, Bluestone JA, Herold KC. Immune Therapy and β-Cell Death in Type 1 Diabetes. Diabetes 2013, 62: 1676-1680. PMID: 23423576, PMCID: PMC3636605, DOI: 10.2337/db12-1207.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodies, Monoclonal, HumanizedCD3 ComplexC-PeptideCytotoxicity Tests, ImmunologicCytotoxicity, ImmunologicDiabetes Mellitus, Type 1DNA MethylationFemaleHumansHypoglycemic AgentsImmunologic FactorsImmunotherapyInsulinInsulin SecretionInsulin-Secreting CellsIslets of LangerhansMalePostprandial PeriodYoung AdultConceptsRecent-onset T1DΒ-cell deathΒ-cellsNondiabetic subjectsImmune therapyType 1 diabetes resultsAnti-CD3 monoclonal antibodyUnmethylated INS DNAC-peptide responseNondiabetic control subjectsΒ-cell functionInsulin-producing β-cellsHigh rateImmune interventionDiabetes resultsControl subjectsClinical trialsPatientsT1DType 1Monoclonal antibodiesDeathTeplizumabINS DNATherapy
2012
Analysis of Human Biologics With a Mouse Skin Transplant Model in Humanized Mice
Waldron-Lynch F, Deng S, Preston-Hurlburt P, Henegariu O, Herold KC. Analysis of Human Biologics With a Mouse Skin Transplant Model in Humanized Mice. American Journal Of Transplantation 2012, 12: 2652-2662. PMID: 22900715, DOI: 10.1111/j.1600-6143.2012.04178.x.Peer-Reviewed Original ResearchConceptsSkin transplant modelGraft rejectionTransplant modelHumanized miceSkin graftsT cellsFunctional human immune responsesMouse skin transplant modelMurine skin transplant modelCentral memory T cellsNOD/SCID/Mouse skin graftsMemory T cellsMonoclonal antibody therapySkin graft rejectionDevelopment of effectorHuman immune responseMHC class IHuman T cellsIpilimumab treatmentAntibody therapySCID/Diffuse infiltrationMouse donorsSerum immunoglobulinsTeplizumab Induces Human Gut-Tropic Regulatory Cells in Humanized Mice and Patients
Waldron-Lynch F, Henegariu O, Deng S, Preston-Hurlburt P, Tooley J, Flavell R, Herold KC. Teplizumab Induces Human Gut-Tropic Regulatory Cells in Humanized Mice and Patients. Science Translational Medicine 2012, 4: 118ra12. PMID: 22277969, PMCID: PMC4131554, DOI: 10.1126/scitranslmed.3003401.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedCD3 ComplexCell MovementDiabetes Mellitus, Type 1Forkhead Transcription FactorsGastrointestinal TractHumansHypoglycemic AgentsInterleukin-10Intestine, SmallL-SelectinMiceMucous MembraneNatalizumabOligonucleotide Array Sequence AnalysisReceptors, CCR6T-Lymphocytes, RegulatoryConceptsHumanized micePeripheral circulationSmall intestineType 1 diabetes mellitusNovel immunologic mechanismIL-10 expressionTreatment of patientsType 1 diabetesSecondary lymph organsHuman immune cellsT cell migrationMechanism of actionGut-tropicImmunologic mechanismsRegulatory cellsDiabetes mellitusImmune therapyInterleukin-10Immune cellsRegulatory cytokinesClinical trialsPreclinical modelsClinical studiesT cellsHuman hematopoietic stem cells
2011
Regulatory T Cells Require Mammalian Target of Rapamycin Signaling To Maintain Both Homeostasis and Alloantigen-Driven Proliferation in Lymphocyte-Replete Mice
Wang Y, Camirand G, Lin Y, Froicu M, Deng S, Shlomchik WD, Lakkis FG, Rothstein DM. Regulatory T Cells Require Mammalian Target of Rapamycin Signaling To Maintain Both Homeostasis and Alloantigen-Driven Proliferation in Lymphocyte-Replete Mice. The Journal Of Immunology 2011, 186: 2809-2818. PMID: 21270412, PMCID: PMC5584652, DOI: 10.4049/jimmunol.0903805.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationCell SurvivalGene Knock-In TechniquesHomeostasisIsoantigensLymphocyte ActivationLymphocyte CountLymphocyte DepletionLymphoid TissueMiceMice, Inbred BALB CMice, Inbred C57BLSignal TransductionSirolimusSkin TransplantationT-Lymphocytes, RegulatoryTOR Serine-Threonine KinasesConceptsPercent of TregRegulatory T cellsHost disease modelT cellsTolerogenic agentsMammalian targetConversion of TregsEffect of RapaFoxp3(-) T cellsNumber of TregsSolid organ transplantationDisease modelsAlloantigen-induced proliferationWild-type miceRAPA therapyTreg depletionTreg survivalCD4 cellsLymphopenic hostsImmunosuppressive drugsTregsOrgan transplantationAnimal modelsBaseline numberTconv
2008
Anti‐CD20 Treatment Prolongs Syngeneic Islet Graft Survival and Delays the Onset of Recurrent Autoimmune Diabetes
Hu C, Deng S, Wong FS, Wen L. Anti‐CD20 Treatment Prolongs Syngeneic Islet Graft Survival and Delays the Onset of Recurrent Autoimmune Diabetes. Annals Of The New York Academy Of Sciences 2008, 1150: 217-219. PMID: 19120299, DOI: 10.1196/annals.1447.032.Peer-Reviewed Original ResearchConceptsImmunosuppressive drug treatmentType 1 diabetesIslet transplantationDrug treatmentLong-term immunosuppressive drug treatmentSyngeneic islet graft survivalB cell depletion therapyT cell-mediated destructionAccepted therapeutic optionB-cell depletionPancreatic islet beta cellsCell-mediated destructionIslet graft survivalSyngeneic islet transplantationPancreatic islet transplantationIslet beta cellsRecurrent AutoimmuneTolerance establishmentGraft survivalNOD miceTherapeutic optionsAutoimmune diseasesCell depletionInsulin treatmentBeta cells