2020
Insulin-Reactive T Cells Convert Diabetogenic Insulin-Reactive VH125 B Cells Into Tolerogenic Cells by Reducing Germinal Center T:B Cell Interactions in NOD Mice
Pearson JA, Li Y, Majewska-Szczepanik M, Guo J, Zhang L, Liu Y, Wong FS, Wen L. Insulin-Reactive T Cells Convert Diabetogenic Insulin-Reactive VH125 B Cells Into Tolerogenic Cells by Reducing Germinal Center T:B Cell Interactions in NOD Mice. Frontiers In Immunology 2020, 11: 585886. PMID: 33262765, PMCID: PMC7688534, DOI: 10.3389/fimmu.2020.585886.Peer-Reviewed Original ResearchConceptsB cell interactionsTransgenic NOD miceNOD miceT cellsB cellsT1D developmentAntigen-specific regulatory T cellsInsulin-reactive B cellsInsulin-reactive T cellsNon-obese diabetic (NOD) miceGerminal center TInsulin-reactive CD4Non-germinal centerCell interactionsCostimulatory molecule expressionRegulatory T cellsType 1 diabetesGC B cellsTolerogenic cellsAdoptive transferDiabetic miceTGFβ secretionMolecule expressionIgG isotypeKey autoantigen
2014
Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens
Kleffel S, Vergani A, Tezza S, Nasr M, Niewczas MA, Wong S, Bassi R, D’Addio F, Schatton T, Abdi R, Atkinson M, Sayegh MH, Wen L, Wasserfall CH, O’Connor K, Fiorina P. Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens. Diabetes 2014, 64: 158-171. PMID: 25187361, PMCID: PMC4274804, DOI: 10.2337/db13-1639.Peer-Reviewed Original ResearchConceptsIslet autoantigensB cellsT1D patientsInterleukin-10IL-10-producing B cellsHyperglycemic nonobese diabetic miceRegulatory B-cell responsesAutoreactive T cell responsesT cell-mediated responsesRole of BregsB-cell depletionRegulatory B cellsNonobese diabetic (NOD) miceNOD mouse modelT cell responsesB cell responsesType 1 diabetesB cell receptorAdoptive transferDiabetic miceAutoimmune diseasesHuman ILHyperglycemic miceMouse modelBregsIRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice
Tan Q, Majewska-Szczepanik M, Zhang X, Szczepanik M, Zhou Z, Wong FS, Wen L. IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice. Diabetes 2014, 63: 2761-2775. PMID: 24696448, PMCID: PMC4113073, DOI: 10.2337/db13-1504.Peer-Reviewed Original ResearchConceptsDiabetogenic T cellsNOD miceRapid progressionT cellsInterleukin-1 receptor-associated kinase MOrgan-specific autoimmune diseasesType 1 diabetes mellitusAnti-insulin autoantibodiesImmunodeficient NOD miceImpaired glucose toleranceAntigen-presenting functionNonobese diabetic (NOD) miceToll-like receptor pathwayAntigen-presenting cellsEnhanced activationType 1 diabetesInnate immune pathwaysIRAK-M deficiencyInnate immune processesInsulin-secreting pancreatic β-cellsPancreatic β-cellsSevere insulitisAutoimmune diabetesDendritic cellsDiabetes mellitus
2012
The Dual Effects of B Cell Depletion on Antigen-Specific T Cells in BDC2.5NOD Mice
Xiang Y, Peng J, Tai N, Hu C, Zhou Z, Wong FS, Wen L. The Dual Effects of B Cell Depletion on Antigen-Specific T Cells in BDC2.5NOD Mice. The Journal Of Immunology 2012, 188: 4747-4758. PMID: 22490442, PMCID: PMC4361183, DOI: 10.4049/jimmunol.1103055.Peer-Reviewed Original ResearchConceptsB-cell depletionCell depletionT cellsB cellsAntigen-specific T cellsAg-specific T cellsBDC2.5 T cellsDiabetogenic T cellsRegulatory T cellsT cell responsesB-cell reconstitutionB-cell regenerationT-cell phenotypeImmune regulatory functionsFuture clinical protocolsΒ-cell lossMultiple injection protocolsAutoimmune diabetesRituximab therapyCytokine profileDiabetic patientsCell reconstitutionTherapeutic effectPreclinical studiesHuman CD20The Role of Gr1+ Cells after Anti-CD20 Treatment in Type 1 Diabetes in Nonobese Diabetic Mice
Hu C, Du W, Zhang X, Wong FS, Wen L. The Role of Gr1+ Cells after Anti-CD20 Treatment in Type 1 Diabetes in Nonobese Diabetic Mice. The Journal Of Immunology 2012, 188: 294-301. PMID: 22140261, PMCID: PMC4361178, DOI: 10.4049/jimmunol.1101590.Peer-Reviewed Original ResearchConceptsType 1 diabetesT cell functionNOD miceCD8 T cell functionRegulatory T cell differentiationAnti-CD20 treatmentPancreatic islet autoimmunityB-cell depletionCell contact-dependent mannerNonobese diabetic (NOD) miceCell functionT cell differentiationContact-dependent mannerDiabetogenic CD4Islet autoimmunityNovel immunotherapiesIL-10Immune toleranceDiabetic miceAutoimmune diseasesCell depletionImmunoregulatory functionsDiabetesMiceDependent manner
2011
IL-10-conditioned dendritic cells prevent autoimmune diabetes in NOD and humanized HLA-DQ8/RIP-B7.1 mice
Tai N, Yasuda H, Xiang Y, Zhang L, Rodriguez-Pinto D, Yokono K, Sherwin R, Wong FS, Nagata M, Wen L. IL-10-conditioned dendritic cells prevent autoimmune diabetes in NOD and humanized HLA-DQ8/RIP-B7.1 mice. Clinical Immunology 2011, 139: 336-349. PMID: 21458378, DOI: 10.1016/j.clim.2011.03.003.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsB7-1 AntigenDendritic CellsDiabetes Mellitus, Type 1Disease Models, AnimalFemaleHLA-DQ AntigensHumansImmune ToleranceImmunophenotypingInsulin-Secreting CellsInterleukin-10Lymphocyte ActivationMaleMiceMice, Inbred BALB CMice, Inbred NODMice, SCIDMice, TransgenicSpecific Pathogen-Free OrganismsT-LymphocytesConceptsRIP-B7.1 miceAutoimmune diabetesIL-10IL-10-treated DCIL-12/23 p40T cell toleranceT cell proliferationDifferent animal modelsNew therapeutic interventionsSpontaneous diabetesRegulatory cellsDendritic cellsImmune toleranceCostimulatory moleculesIL-6IL-4T cellsAnimal modelsCell toleranceTherapeutic interventionsDiabetesCell proliferationT1D.MiceCells
2010
Immunotargeting of insulin reactive CD8 T cells to prevent Diabetes
Scott G, Fishman S, Siew L, Margalit A, Chapman S, Chervonsky A, Wen L, Gross G, Wong F. Immunotargeting of insulin reactive CD8 T cells to prevent Diabetes. Journal Of Autoimmunity 2010, 35: 390-397. PMID: 20850948, DOI: 10.1016/j.jaut.2010.08.005.Peer-Reviewed Original ResearchConceptsCD8 T cellsT cellsNOD miceAdoptive transferInsulin-reactive T cellsReactive CD8 T cellsInsulin-producing beta cellsPancreatic lymph nodesYoung NOD miceOnset of diabetesTransgenic T cellsCourse of diseaseType 1 diabetesFas-Fas ligand pathwayRelease of perforinSpontaneous diabetesAutoreactive CD4Lymph nodesImmune destructionLower incidenceBeta cellsDiabetesLigand pathwayPancreatic isletsTarget cells
2009
Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes
Wong FS, Siew LK, Scott G, Thomas IJ, Chapman S, Viret C, Wen L. Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes. Diabetes 2009, 58: 1156-1164. PMID: 19208910, PMCID: PMC2671054, DOI: 10.2337/db08-0800.Peer-Reviewed Original ResearchConceptsCD8 T cellsCD8 T cell clonesT cell clonesT cellsTransgenic miceT cell receptor transgenic miceAutoimmune CD8 T cellsInsulin-reactive T cellsCD8 single-positive thymocytesNonobese diabetic (NOD) miceReceptor transgenic miceDevelopment of autoimmuneTCR transgenic miceTransgenic T cellsThymic negative selectionSingle-positive thymocytesThymic insulin expressionDiabetogenic capacityIslet infiltratesSpontaneous diabetesPeripheral lymphClonotypic TCRDiabetic miceImmunodeficient NODNaïve phenotype
2008
IFN‐α Can Both Protect against and Promote the Development of Type 1 Diabetes
Wong F, Wen L. IFN‐α Can Both Protect against and Promote the Development of Type 1 Diabetes. Annals Of The New York Academy Of Sciences 2008, 1150: 187-189. PMID: 19120292, DOI: 10.1196/annals.1447.031.Peer-Reviewed Original ResearchDeveloping a Novel Model System to Target Insulin‐Reactive CD8 T Cells
Scott G, Fishman S, Margalit A, Siew L, Chapman S, Wen L, Gross G, Wong F. Developing a Novel Model System to Target Insulin‐Reactive CD8 T Cells. Annals Of The New York Academy Of Sciences 2008, 1150: 54-58. PMID: 19120267, DOI: 10.1196/annals.1447.040.Peer-Reviewed Original Research
2007
Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice
Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik MJ, Wen L. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. Journal Of Clinical Investigation 2007, 117: 3857-3867. PMID: 18060033, PMCID: PMC2096456, DOI: 10.1172/jci32405.Peer-Reviewed Original ResearchConceptsB-cell depletionCell depletionB cellsNOD miceTherapeutic B cell depletionTransgenic NOD miceRegulatory B cellsLong-term remissionExpansion of TregsOnset of diabetesType 1 diabetesReverse diabetesClinical efficacyDiabetic miceAutoimmune diseasesFrank hyperglycemiaAntigen presentationT cellsHuman CD20DiabetesTherapeutic actionMiceClinical hyperglycemiaDiseasePotential mechanismsCD86 Has Sustained Costimulatory Effects on CD8 T Cells
Thomas IJ, de Marquesini L, Ravanan R, Smith RM, Guerder S, Flavell RA, Wraith DC, Wen L, Wong FS. CD86 Has Sustained Costimulatory Effects on CD8 T Cells. The Journal Of Immunology 2007, 179: 5936-5946. PMID: 17947667, PMCID: PMC2629533, DOI: 10.4049/jimmunol.179.9.5936.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB7-1 AntigenB7-2 AntigenCD8-Positive T-LymphocytesCell DifferentiationCell ProliferationCells, CulturedCytokinesDiabetes MellitusGene Expression RegulationHealthHumansIslets of Langerhans TransplantationMiceMice, TransgenicPromoter Regions, GeneticRatsReceptor, InsulinSurvival RateTime FactorsTransgenesConceptsCD8 T cellsT cellsT cell activationCD86 costimulationCell activationCytotoxic T-cell activationTransfer of diabetesOld NOD miceInhibitory molecule expressionRat insulin promoterGreater sustained activityNOD isletsRecurrent diabetesNOD miceDiabetes onsetDiabetic miceCostimulatory moleculesCTLA-4Cytokine secretionMolecule expressionCostimulatory effectImmune responseCD80CD86CD80 costimulation
2006
TGF-β signaling is required for the function of insulin-reactive T regulatory cells
Du W, Wong FS, Li MO, Peng J, Qi H, Flavell RA, Sherwin R, Wen L. TGF-β signaling is required for the function of insulin-reactive T regulatory cells. Journal Of Clinical Investigation 2006, 116: 1360-1370. PMID: 16670772, PMCID: PMC1451206, DOI: 10.1172/jci27030.Peer-Reviewed Original ResearchConceptsT cellsNOD miceRegulatory cellsDominant negative TGF-beta receptor type IITransgenic miceTCR transgenic T cellsTGF-beta receptor type IIDiabetic NOD miceDiabetogenic spleen cellsDiabetogenic T cellsTCR transgenic miceTransgenic T cellsReceptor type IIBDC2.5 miceAdoptive transferTGF-beta signalingSpleen cellsParacrine mannerGranule antigensAutocrine mannerSuppressive propertiesDiabetesMiceTarget cellsSpontaneous development
2004
Investigation of the Role of B-Cells in Type 1 Diabetes in the NOD Mouse
Wong FS, Wen L, Tang M, Ramanathan M, Visintin I, Daugherty J, Hannum LG, Janeway CA, Shlomchik MJ. Investigation of the Role of B-Cells in Type 1 Diabetes in the NOD Mouse. Diabetes 2004, 53: 2581-2587. PMID: 15448087, DOI: 10.2337/diabetes.53.10.2581.Peer-Reviewed Original ResearchConceptsB cell-deficient miceAntigen-presenting functionType 1 diabetesB cellsNOD miceNormal NOD miceIncidence of diabetesDevelopment of diabetesT cell repertoireB cell repertoireAntigen presentationDiabetesAntibody productionMiceImmunoglobulin transgenesReduced abilityCell surfaceInsulitisAutoantibodiesIncidenceImmunoglobulinAntibodiesWhat can the HLA transgenic mouse tell us about autoimmune diabetes?
Wong F, Wen L. What can the HLA transgenic mouse tell us about autoimmune diabetes? Diabetologia 2004, 47: 1476-1487. PMID: 15349728, DOI: 10.1007/s00125-004-1505-5.Peer-Reviewed Original ResearchConceptsHLA transgenic miceType 1 diabetes mellitusTransgenic miceDiabetes mellitusHLA class II allelesCD4 T lymphocytesAntigen-presenting moleculesClass II allelesPeptide-MHC complexesStudies of micePutative autoantigenParticular HLAT lymphocytesHLA moleculesPeptide antigensMHC complexesMiceDiseasePolygenic diseaseMellitusVivo roleInsultIntracellular processingImmunotherapyDiabetes
2003
Autoimmune diabetes in HLA‐DR3/DQ8 transgenic mice expressing the co‐stimulatory molecule B7‐1 in the β cells of islets of Langerhans
Rajagopalan G, Kudva YC, Chen L, Wen L, David CS. Autoimmune diabetes in HLA‐DR3/DQ8 transgenic mice expressing the co‐stimulatory molecule B7‐1 in the β cells of islets of Langerhans. International Immunology 2003, 15: 1035-1044. PMID: 12917255, DOI: 10.1093/intimm/dxg103.Peer-Reviewed Original ResearchConceptsCo-stimulatory molecules B7-1Incidence of diabetesTransgenic miceB7-1Autoimmune diabetesHLA-DQ8HLA-DR3T cellsBeta cellsBeta-cell toxin streptozotocinHLA class II associationsDQ8 transgenic micePresence of DR3HLA transgenic miceAntibody-mediated depletionPathogenesis of T1D.Class II associationsHLA class IIWhole-body irradiationPancreatic beta cellsNon-specific activationSpontaneous diabetesToxin streptozotocinDiabetogenic potentialSTZ treatmentThe study of HLA class II and autoimmune diabetes.
Wong F, Wen L. The study of HLA class II and autoimmune diabetes. 2003, 3: 1-15. PMID: 12558070, DOI: 10.2174/1566524033361591.Peer-Reviewed Original ResearchConceptsHLA moleculesTransgenic miceHuman leucocyte antigens DR3HLA transgenic miceCD4 T lymphocytesHLA class IIAntigen-specific cellsT cell epitopesMHC-peptide complexesPeptide-MHC complexesPutative autoantigenDiabetes mellitusAutoimmune diseasesAntigens DR3T lymphocytesCell epitopesClass IIPeptide antigensMajor histocompatibility complex class II lociMHC complexesDiseaseClass II lociDevelopment of reagentsMiceFurther studies
2001
The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model
Wen L, Chen N, Tang J, Sherwin R, Wong F. The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. Journal Of Clinical Investigation 2001, 107: 871-880. PMID: 11285306, PMCID: PMC199575, DOI: 10.1172/jci11708.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Marrow CellsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell DifferentiationDiabetes Mellitus, Type 1Disease Models, AnimalFemaleGene ExpressionHistocompatibility Antigens Class IIHLA-DQ AntigensHLA-DR4 AntigenIncidenceInsulinMaleMiceMice, Inbred C57BLMice, TransgenicMicrosatellite RepeatsPancreasSialadenitisSpleenTh2 CellsTransgenesConceptsMHC class II moleculesSpontaneous diabetesClass II moleculesTransgenic miceT cellsHLA-DQ8Diabetogenic effectMouse MHC class II moleculesHLA-DR transgenic miceTh2-like immune responsesHuman type 1 diabetesAutoreactive T cellsDouble transgenic miceType 1 diabetesC57BL/6 transgenic miceTh2-like phenotypePancreatic beta cellsExpression of DR4DQ8 allelesDiabetes developmentCostimulatory moleculesHLA-DQImmune responseBeta cellsDiabetesType 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model
Abraham R, Wen L, Marietta E, David C. Type 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model. The Journal Of Immunology 2001, 166: 1370-1379. PMID: 11145722, DOI: 10.4049/jimmunol.166.2.1370.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAmino Acid SequenceAnimalsAntibody SpecificityCells, CulturedCytokinesDiabetes Mellitus, Type 1Disease Models, AnimalEpitopes, T-LymphocyteGenes, MHC Class IIGenetic Predisposition to DiseaseGlutamate DecarboxylaseHLA-DQ AntigensHLA-DR3 AntigenHumansImmunophenotypingIslets of LangerhansIsoenzymesLymphocyte ActivationMiceMice, Inbred C57BLMice, TransgenicMolecular Sequence DataRatsT-Lymphocyte SubsetsConceptsGlutamic acid decarboxylaseGAD 65T cellsDQ8 miceMixed Th1/Th2 cytokine profileEndogenous MHC class IISpontaneous T-cell reactivityTh1/Th2 cytokine profileGlutamic acid decarboxylase 65Self-reactive responsesT cell reactivityTh2 cytokine profileAutoantigen glutamic acid decarboxylase 65Type 1 diabetesMHC class IIDiabetes-associated genesCytokine profileIslet autoantigensHLA-DR3Immune toleranceHLA-DQ6Cell reactivitySelf-AgImmune responseHLA alleles
2000
In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes
Wen L, Wong F, Tang J, Chen N, Altieri M, David C, Flavell R, Sherwin R. In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes. Journal Of Experimental Medicine 2000, 191: 97-104. PMID: 10620608, PMCID: PMC2195792, DOI: 10.1084/jem.191.1.97.Peer-Reviewed Original ResearchConceptsClass II moleculesMHC class II moleculesGlutamic acid decarboxylaseRat insulin promoterSpontaneous diabetesB7-1T cellsBeta cellsMouse MHC class II moleculesTransgenic miceHuman histocompatibility leukocyte antigenHuman type 1 diabetesMajor histocompatibility complex (MHC) class II moleculesCostimulatory molecules B7-1Human MHC class II moleculesVivo evidenceHistocompatibility leukocyte antigenDevelopment of diabetesType 1 diabetesMHC class IIC57BL/6 transgenic miceMurine MHC class IIPancreatic beta cellsVivo experimental evidenceDiabetogenic role