2020
Transcriptomic and clonal characterization of T cells in the human central nervous system
Pappalardo JL, Zhang L, Pecsok MK, Perlman K, Zografou C, Raddassi K, Abulaban A, Krishnaswamy S, Antel J, van Dijk D, Hafler DA. Transcriptomic and clonal characterization of T cells in the human central nervous system. Science Immunology 2020, 5 PMID: 32948672, PMCID: PMC8567322, DOI: 10.1126/sciimmunol.abb8786.Peer-Reviewed Original ResearchMeSH KeywordsAdultCentral Nervous SystemHumansMultiple Sclerosis, Relapsing-RemittingT-LymphocytesTranscriptomeConceptsCentral nervous systemCSF of patientsT cellsCerebrospinal fluidMultiple sclerosisImmune surveillanceNervous systemCSF T cellsHuman central nervous systemHealthy human donorsT cell activationImmune dysfunctionNeuroinflammatory diseasesCytotoxic capacityHealthy donorsHealthy individualsCell activationHuman donorsTissue adaptationPatientsClonal characterizationExpression of genesCellsSurveillanceFurther characterization
2018
Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity
Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DA. Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nature Immunology 2018, 19: 1391-1402. PMID: 30374130, PMCID: PMC6240373, DOI: 10.1038/s41590-018-0236-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmunityBeta CateninGene Expression RegulationHumansInflammationInterferon-gammaInterleukin-10Mice, Inbred C57BLMultiple Sclerosis, Relapsing-RemittingReceptors, Prostaglandin E, EP2 SubtypeT-Lymphocytes, RegulatoryConceptsProstaglandin E receptor 2Regulatory T cellsTreg cellsT cellsAnti-inflammatory cytokine productionIL-10 productionPeripheral immune toleranceIL-10 expressionΒ-cateninE receptor 2Treg subpopulationsTreg phenotypeIL-10Cytokines IFNImmune toleranceTreg signatureCytokine signatureMultiple sclerosisAutoimmune diseasesCytokine productionInflammatory environmentLethal autoimmunityReceptor 2Activated β-cateninIFNFingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo
Dominguez-Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Hafler DA. Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo. Journal Of Autoimmunity 2018, 96: 40-49. PMID: 30122421, PMCID: PMC7882197, DOI: 10.1016/j.jaut.2018.08.002.Peer-Reviewed Original ResearchMeSH KeywordsAdultCell PlasticityFemaleFingolimod HydrochlorideHumansImmunologic FactorsImmunophenotypingLymphocyte ActivationMaleMiddle AgedMultiple Sclerosis, Relapsing-RemittingTh1 CellsTh17 CellsT-Lymphocytes, RegulatoryYoung AdultConceptsT cellsMultiple sclerosisT cell effector phenotypeRelapsing-remitting multiple sclerosisRegulatory T cell populationTh1-like phenotypeRegulatory T cellsPro-inflammatory cytokinesT-cell phenotypeT cell populationsExpression of Th1Immune cell functionRegulatory T cell plasticityT cell plasticityCentral nervous systemExpression of markersCell migratory capacityImportant immunomodulatory functionsExcessive Th1Fingolimod treatmentExhaustion markersTh17 cytokinesEffector phenotypeLymph nodesSerum levels
2013
Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing– remitting multiple sclerosis
Van Haren K, Tomooka BH, Kidd BA, Banwell B, Bar-Or A, Chitnis T, Tenembaum SN, Pohl D, Rostasy K, Dale RC, O’Connor K, Hafler DA, Steinman L, Robinson WH. Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing– remitting multiple sclerosis. Multiple Sclerosis Journal 2013, 19: 1726-1733. PMID: 23612879, PMCID: PMC4411183, DOI: 10.1177/1352458513485653.Peer-Reviewed Original ResearchConceptsAcute disseminated encephalomyelitisMyelin basic proteinDisseminated encephalomyelitisMyelin peptidesMultiple sclerosisIgM autoantibodiesIsotype-specific secondary antibodiesPediatric acute disseminated encephalomyelitisRelapsing-remitting multiple sclerosisPediatric multiple sclerosisProteolipid proteinMicroarrays softwareBasic proteinMyelin antigensLaboratory featuresPeptide autoantibodiesMS seraSerum autoantibodiesIgG autoantibodiesAutoantibody biomarkersSerum IgGOligodendrocyte-specific proteinAutoantibody reactivityAdult MSAutoantibodies
2011
Identification of T helper type 1–like, Foxp3+ regulatory T cells in human autoimmune disease
Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1–like, Foxp3+ regulatory T cells in human autoimmune disease. Nature Medicine 2011, 17: 673-675. PMID: 21540856, PMCID: PMC3675886, DOI: 10.1038/nm.2389.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesForkhead Transcription FactorsHumansImmunity, CellularInterferon-betaInterferon-gammaInterleukin-12Multiple Sclerosis, Relapsing-RemittingTh1 CellsT-Lymphocytes, RegulatoryConceptsTreg cellsT helper type 1Regulatory T cellsT regulatory (Treg) cellsHelper type 1T helper typeHuman autoimmune diseasesHuman Treg cellsRegulatory cellsIL-12Multiple sclerosisAutoimmune diseasesPeripheral bloodHelper typeT cellsSuppressive activityType 1Functional plasticityConsiderable phenotypicCellsSclerosisIFNDiseaseMiceBloodInterferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis
Vosslamber S, van der Voort LF, van den Elskamp IJ, Heijmans R, Aubin C, Uitdehaag BM, Crusius JB, van der PouwKraan T, Comabella M, Montalban X, Hafler DA, De Jager PL, Killestein J, Polman CH, Verweij CL. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis. Genes & Immunity 2011, 12: 466-472. PMID: 21471993, DOI: 10.1038/gene.2011.18.Peer-Reviewed Original ResearchMeSH KeywordsAdultBiomarkersCohort StudiesFemaleGene ExpressionGenetic VariationGenotypeHumansInterferon Regulatory FactorsInterferon-betaMagnetic Resonance ImagingMaleMultiple Sclerosis, Relapsing-RemittingPolymorphism, Single NucleotideTreatment OutcomeConceptsRelapsing-remitting multiple sclerosisNon-responder statusInterferon regulatory factor 5IFNβ treatmentMultiple sclerosisT2 lesionsClinical outcomesMore magnetic resonance imagingMore T2 lesionsStart of therapyGene variantsInterferon-β TherapyIFN response genesRegulatory factor 5Poor pharmacological responseMagnetic resonance imagingIFNβ therapyClinical responseFirst relapseIndependent cohortPharmacological responseClinical relevanceG allelePatientsResonance imaging
2010
A Randomized Controlled Double-Masked Trial of Albuterol Add-on Therapy in Patients With Multiple Sclerosis
Khoury SJ, Healy BC, Kivisäkk P, Viglietta V, Egorova S, Guttmann CR, Wedgwood JF, Hafler DA, Weiner HL, Buckle G, Cook S, Reddy S. A Randomized Controlled Double-Masked Trial of Albuterol Add-on Therapy in Patients With Multiple Sclerosis. JAMA Neurology 2010, 67: 1055-1061. PMID: 20837847, PMCID: PMC2954052, DOI: 10.1001/archneurol.2010.222.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAdrenergic beta-AgonistsAdultAlbuterolDouble-Blind MethodDrug Administration ScheduleDrug Therapy, CombinationFemaleGlatiramer AcetateHumansInterferon-gammaInterleukin-13Logistic ModelsMaleMiddle AgedMultiple Sclerosis, Relapsing-RemittingOdds RatioPeptidesPilot ProjectsTreatment OutcomeConceptsMultiple Sclerosis Functional CompositeRelapsing-remitting multiple sclerosisGlatiramer acetateMultiple sclerosisClinical trialsAlbuterol groupTime pointsOral doseIL-13Subcutaneous injectionHelper T-cell subtypes 1Double-masked clinical trialGlatiramer acetate treatmentImmunologic end pointsMasked clinical trialEffects of albuterolIL-12 expressionIL-13 productionStudy time pointsΒ2-adrenergic agonistAlbuterol treatmentAcetate therapyAdverse eventsFirst relapseImmunologic effects
2008
CTLA4Ig treatment in patients with multiple sclerosis
Viglietta V, Bourcier K, Buckle GJ, Healy B, Weiner HL, Hafler DA, Egorova S, Guttmann CR, Rusche JR, Khoury SJ. CTLA4Ig treatment in patients with multiple sclerosis. Neurology 2008, 71: 917-924. PMID: 18794494, DOI: 10.1212/01.wnl.0000325915.00112.61.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptBrainCohort StudiesDose-Response Relationship, DrugHumansImmune SystemImmunoconjugatesImmunosuppressive AgentsInterferon-gammaMagnetic Resonance ImagingMultiple Sclerosis, Relapsing-RemittingMyelin Basic ProteinTime FactorsConceptsMultiple sclerosisCostimulatory pathwayPhase 1 dose-escalation studyT cell-mediated autoimmune diseaseCell-mediated autoimmune diseaseRelapsing-remitting multiple sclerosisT-cell costimulatory pathwaysCostimulatory molecule interactionsMonths of infusionDose-escalation studyInterferon-gamma productionT cell activationOriginal therapeutic approachAdverse eventsImmunologic assessmentImmunologic effectsCTLA4Ig treatmentChronic inflammationAutoimmune diseasesInflammatory processT cellsImmune responseTherapeutic approachesCTLA4IgExtension studyCytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells
De Jager PL, Rossin E, Pyne S, Tamayo P, Ottoboni L, Viglietta V, Weiner M, Soler D, Izmailova E, Faron-Yowe L, O’Brien C, Freeman S, Granados S, Parker A, Roubenoff R, Mesirov JP, Khoury SJ, Hafler DA, Weiner HL. Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells. Brain 2008, 131: 1701-1711. PMID: 18567923, PMCID: PMC2730047, DOI: 10.1093/brain/awn118.Peer-Reviewed Original ResearchMeSH KeywordsAdultCD8-Positive T-LymphocytesDemyelinating DiseasesFemaleFlow CytometryHumansImmunophenotypingMaleMiddle AgedMultiple Sclerosis, Relapsing-RemittingPrognosisProspective StudiesT-Lymphocyte SubsetsConceptsRelapsing-remitting MSImmunological profileRRMS subjectsPeripheral bloodUntreated subjectsNatural killer cell profileComprehensive Longitudinal InvestigationAbsence of treatmentCell surface markersCIS subjectsDemyelinating diseaseDemyelination syndromeWomen's HospitalHealthy controlsCytometric profilingCell profilesMonoclonal antibodiesExtension phaseFresh bloodBiomarker discovery effortsDistinct subsetsBloodCell populationsGating strategyHospital
2004
Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules
Mycko MP, Waldner H, Anderson DE, Bourcier KD, Wucherpfennig KW, Kuchroo VK, Hafler DA. Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules. The Journal Of Immunology 2004, 173: 1689-1698. PMID: 15265898, DOI: 10.4049/jimmunol.173.3.1689.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsAntigen PresentationAutoantigensCD4 AntigensCross ReactionsEncephalomyelitis, Autoimmune, ExperimentalHLA-DR alpha-ChainsHLA-DR AntigensHLA-DRB1 ChainsHumansHybridomasL CellsLymphocyte ActivationMembrane ProteinsMiceMolecular Sequence DataMultiple Sclerosis, Relapsing-RemittingMyelin Basic ProteinPeptide FragmentsPhosphorylationProtein Processing, Post-TranslationalReceptors, Antigen, T-CellReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsTransfectionConceptsAutoreactive T cellsMHC class II moleculesClass II moleculesT cellsSpontaneous experimental autoimmune encephalomyelitisRelapsing-remitting multiple sclerosisDifferent MHC class II moleculesExperimental autoimmune encephalomyelitisAltered peptide ligandTh cell clonesT cell hybridomasMyelin basic proteinAutoimmune encephalomyelitisMultiple sclerosisSelf antigensCD4 coreceptorRestriction elementsHealthy individualsDiseased patientsHuman TCRPatientsTCR responsesCell clonesCell hybridomasPeptide ligands
2003
In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis
Schmied M, Duda PW, Krieger JI, Trollmo C, Hafler DA. In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis. Clinical Immunology 2003, 106: 163-174. PMID: 12706402, DOI: 10.1016/s1521-6616(03)00020-2.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntigen PresentationCytokinesDose-Response Relationship, DrugFemaleGlatiramer AcetateHumansImmune ToleranceInjections, SubcutaneousInterleukin-2MaleMultiple Sclerosis, Relapsing-RemittingPeptidesRecombinant ProteinsT-LymphocytesConceptsGA-reactive T cellsT cell reactivityT cellsRR-MSMultiple sclerosisCell reactivityT cell peripheral toleranceTh2-type T cellsT cell frequenciesMonths of treatmentT cell hyporesponsivenessT cell populationsT cell nonresponsivenessT cell anergyHyporesponsive T cellsMechanism of actionMyelin antigensGlatiramer acetatePeripheral toleranceCell hyporesponsivenessPeripheral bloodClonal eliminationIL-2Cell anergySubcutaneous administrationActivated CD8+ T cells in secondary progressive MS secrete lymphotoxin
Buckle GJ, Höllsberg P, Hafler DA. Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin. Neurology 2003, 60: 702-705. PMID: 12601116, DOI: 10.1212/01.wnl.0000048204.89346.30.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodiesCD3 ComplexCD8-Positive T-LymphocytesCell DivisionCell SeparationCells, CulturedCytokinesFemaleFlow CytometryGene FrequencyHumansLymphotoxin-alphaMaleMiddle AgedMultiple Sclerosis, Chronic ProgressiveMultiple Sclerosis, Relapsing-RemittingPolymorphism, Single NucleotideReference ValuesConceptsT cellsNormal controlsSecondary progressive MSCytokine secretion profileFunctional activation statesLymphotoxin secretionProgressive MSActivated CD8Cytokine secretionSecretion profileCytokine genesCD8SecretionSignificant differencesPatientsSignificant increaseActivation stateSingle nucleotide polymorphism analysisPolymorphism analysisNucleotide polymorphism analysisCells
2001
Decreases in Interleukin-4 Secretion by Invariant CD4−CD8−Vα24JαQ T Cells in Peripheral Blood of Patients with Relapsing–Remitting Multiple Sclerosis
Gausling R, Trollmo C, Hafler D. Decreases in Interleukin-4 Secretion by Invariant CD4−CD8−Vα24JαQ T Cells in Peripheral Blood of Patients with Relapsing–Remitting Multiple Sclerosis. Clinical Immunology 2001, 98: 11-17. PMID: 11141321, DOI: 10.1006/clim.2000.4942.Peer-Reviewed Original ResearchMeSH KeywordsAdultCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesClone CellsHumansInterleukin-4MaleMiddle AgedMultiple Sclerosis, Relapsing-RemittingConceptsRelapsing-remitting multiple sclerosisT cell receptorIFN-gamma secretionMultiple sclerosisT cell clonesT cellsCytokine profilePeripheral bloodIL-4Cell clonesProgressive multiple sclerosisRR-MS patientsCytokine secretion patternsRelapsing-remitting MSInterleukin-4 secretionT cell functionalityCytokine secretionHealthy controlsSecretion patternPatientsCP-MSImmune systemControl individualsCell receptorSecretion
2000
Human and Murine CD4 T Cell Reactivity to a Complex Antigen: Recognition of the Synthetic Random Polypeptide Glatiramer Acetate
Duda P, Krieger J, Schmied M, Balentine C, Hafler D. Human and Murine CD4 T Cell Reactivity to a Complex Antigen: Recognition of the Synthetic Random Polypeptide Glatiramer Acetate. The Journal Of Immunology 2000, 165: 7300-7307. PMID: 11120865, DOI: 10.4049/jimmunol.165.12.7300.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsCD4-Positive T-LymphocytesCell Line, TransformedCell SeparationClone CellsDose-Response Relationship, ImmunologicFemaleGlatiramer AcetateHematopoietic Stem CellsHLA-DR AntigensHumansImmunizationImmunologic MemoryImmunomagnetic SeparationInfant, NewbornLeukocytes, MononuclearLymphocyte ActivationLymphocyte CountMiceMice, Inbred BALB CMice, Inbred C57BLMultiple Sclerosis, Relapsing-RemittingPeptidesSpleenTh1 CellsTh2 CellsConceptsT cell populationsHLA class II DRGlatiramer acetateT cell proliferationClass II DRII DRT cellsCD4 T cell reactivityGA-reactive T cellsHuman T cell proliferative responsesT cell precursor frequencyCell populationsSpecific human T cell clonesT cell proliferative responsesHuman T cell clonesMemory T cellsT cell reactivityMultiple sclerosis patientsRecent clinical findingsCell precursor frequencyCell proliferative responsesCell proliferationT cell clonesDose-dependent proliferationHealthy human adultsA novel population of B7‐1+ T cells producing intracellular IL‐4 is decreased in patients with multiple sclerosis
Kipp B, Bar‐Or A, Gausling R, Oliveira E, Fruhan S, Stuart W, Hafler D. A novel population of B7‐1+ T cells producing intracellular IL‐4 is decreased in patients with multiple sclerosis. European Journal Of Immunology 2000, 30: 2092-2100. PMID: 10940899, DOI: 10.1002/1521-4141(200007)30:7<2092::aid-immu2092>3.0.co;2-7.Peer-Reviewed Original ResearchConceptsT cell receptorIntracellular IL-4Multiple sclerosisT cellsB7-1IL-4Autoimmune diseasesTNF-alphaIFN-gammaIL-4-producing T cellsLittle IL-4Immunoregulatory T cellsIL-4 productionIntracellular IFN-gammaT cell populationsLittle IFN-gammaNovel populationDiverse TCR repertoireMHC class IIHuman T cellsShort-term cultureCell surface moleculesTCR repertoireNormal subjectsPatients