2014
Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms
Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C, Wu C, Baloglu E, Schmidt D, Ramesh R, Lobera M, Sundrud MS, Tsai PY, Xiang Z, Wang J, Xu Y, Lin X, Kretschmer K, Rahl PB, Young RA, Zhong Z, Hafler DA, Regev A, Ghosh S, Marson A, Kuchroo VK. Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms. Immunity 2014, 40: 477-489. PMID: 24745332, PMCID: PMC4066874, DOI: 10.1016/j.immuni.2014.04.004.Peer-Reviewed Original ResearchMeSH KeywordsAndrostenolsAnimalsBenzeneacetamidesBenzhydryl CompoundsCell DifferentiationCell Line, TumorCell LineageCytokinesDigoxinEncephalomyelitis, Autoimmune, ExperimentalGene Regulatory NetworksHeterocyclic Compounds, 4 or More RingsHumansMiceMice, Inbred C57BLMice, KnockoutMultiple SclerosisMyelin-Oligodendrocyte GlycoproteinNuclear Receptor Subfamily 1, Group F, Member 3Peptide FragmentsProtein BindingStructure-Activity RelationshipSystems BiologyTh17 CellsT-Lymphocyte SubsetsTranscription, GeneticTranscriptional ActivationConceptsTranscriptional networksSignature genesCis-regulatory sitesStrong transcriptional effectsInterconnected regulatory networkCell signature genesSystem-scale analysisTranscriptional regulationDirect repressorTarget lociTranscriptome sequencingRegulatory networksDNA bindingTranscriptional effectsCell lineagesCell differentiationT-cell lineageDirect activatorDivergent mechanismsT cell differentiationSpecific inhibitorDistinct mechanismsPotential therapeutic compoundsGenesRetinoid-related orphan receptor gamma t
2013
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013, 496: 518-522. PMID: 23467095, PMCID: PMC3746493, DOI: 10.1038/nature11868.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedEncephalomyelitis, Autoimmune, ExperimentalGene SilencingGranulocyte-Macrophage Colony-Stimulating FactorHumansImmediate-Early ProteinsInterleukin-2MAP Kinase Signaling SystemMiceMice, Inbred C57BLP38 Mitogen-Activated Protein KinasesPhenotypeProtein Serine-Threonine KinasesSodium Chloride, DietaryTh17 CellsTranscription FactorsTumor Necrosis Factor-alpha
2009
T-Cells in Multiple Sclerosis
Severson C, Hafler DA. T-Cells in Multiple Sclerosis. 2009, 51: 1-24. PMID: 19582415, DOI: 10.1007/400_2009_12.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmunityCentral Nervous SystemEncephalomyelitis, Autoimmune, ExperimentalHumansLymphocyte ActivationMiceMultiple SclerosisT-Lymphocyte SubsetsT-LymphocytesT-Lymphocytes, RegulatoryConceptsMultiple sclerosisT cellsMultifocal demyelinating diseaseMultiple cell subtypesRegulatory T cellsT cell subsetsT cell functionCentral nervous systemRational therapeutic strategiesT cell activationDemyelinating diseaseMS pathogenesisMS pathophysiologyCell subsetsAdaptive immunityEffective treatmentTherapeutic strategiesNervous systemCell activationCell subtypesEvidence implicateSpecific toleranceFunctional defectsIntrinsic cellsCell function
2007
Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells
Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA. Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells. Science 2007, 318: 1141-1143. PMID: 18006747, DOI: 10.1126/science.1148536.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesCD11b AntigenCentral Nervous System NeoplasmsDendritic CellsEncephalomyelitis, Autoimmune, ExperimentalGalectinsGlioblastomaHepatitis A Virus Cellular Receptor 2HumansImmunity, InnateInflammation MediatorsLipopolysaccharidesMacrophagesMembrane ProteinsMiceMicrogliaMultiple SclerosisRatsReceptors, ImmunologicReceptors, VirusSignal TransductionTh1 CellsT-LymphocytesToll-Like ReceptorsConceptsImmune receptor Tim-3Tim-3Immune cellsT helper 1 cellsAdaptive immune cellsInnate immune cellsToll-like receptorsInduced Immune ResponsesInnate immune systemTh1 immunityDendritic cellsTissue inflammationInflammatory conditionsT cellsImmune responseImmune systemImportant mediatorAntibody agonistsInflammationCell typesLatter findingNumerous pathwaysCellsDifferential expressionCD4Protective and therapeutic role for αB-crystallin in autoimmune demyelination
Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O’Conner K, Hafler DA, Sobel RA, Robinson WH, Steinman L. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 2007, 448: 474-479. PMID: 17568699, DOI: 10.1038/nature05935.Peer-Reviewed Original ResearchMeSH KeywordsAlpha-Crystallin B ChainAnimalsApoptosisAstrocytesCaspase 3Encephalomyelitis, Autoimmune, ExperimentalHumansInflammationMacrophagesMAP Kinase Signaling SystemMiceMultiple SclerosisMyelin SheathNeurogliaNeuroprotective AgentsNF-kappa BT-Lymphocytes, Helper-Inducer
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
1999
The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis
Hafler DA. The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis. Journal Of Clinical Investigation 1999, 104: 527-529. PMID: 10487765, PMCID: PMC483283, DOI: 10.1172/jci8193.Peer-Reviewed Original ResearchAnimalsAntigen PresentationAntigens, ViralAutoantigensAutoimmune DiseasesCardiovirus InfectionsCross ReactionsDemyelinating DiseasesDisease Models, AnimalDisease ProgressionEncephalomyelitis, Autoimmune, ExperimentalEpitopesHuman T-lymphotropic virus 1HumansMiceMicrogliaModels, ImmunologicalMolecular MimicryMultiple SclerosisMyelin ProteinsParaparesis, Tropical SpasticTheilovirusT-Lymphocyte SubsetsVirus DiseasesCross-Reactivity of Borrelia burgdorferi and Myelin Basic Protein-Specific T Cells Is Not Observed in Borrelial Encephalomyelitis
Pohl-Koppe A, Logigian E, Steere A, Hafler D. Cross-Reactivity of Borrelia burgdorferi and Myelin Basic Protein-Specific T Cells Is Not Observed in Borrelial Encephalomyelitis. Cellular Immunology 1999, 194: 118-123. PMID: 10357888, DOI: 10.1006/cimm.1999.1495.Peer-Reviewed Original ResearchMeSH KeywordsBorrelia burgdorferi GroupCross ReactionsEncephalomyelitis, Autoimmune, ExperimentalHumansLyme DiseaseMyelin Basic ProteinT-LymphocytesConceptsMyelin basic proteinT cell linesB. burgdorferiMyelin basic protein-specific T cellsT cell autoimmune responsesShort-term T cell linesLate Lyme diseaseT cell responsesT cell clonesWhite matter diseaseMyelin antigensTransverse myelitisRare manifestationAutoimmune responseMultiple sclerosisPathogenetic roleHealthy controlsT cellsLike diseaseWhite matterPatientsEncephalomyelitisLyme borreliosisLyme diseaseBorrelia burgdorferi
1998
Myelin basic protein reactive Th2 T cells are found in acute disseminated encephalomyelitis
Pohl-Koppe A, Burchett S, Thiele E, Hafler D. Myelin basic protein reactive Th2 T cells are found in acute disseminated encephalomyelitis. Journal Of Neuroimmunology 1998, 91: 19-27. PMID: 9846815, DOI: 10.1016/s0165-5728(98)00125-8.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, ViralAutoimmunityChildChild, PreschoolDemyelinating DiseasesEncephalomyelitis, Acute DisseminatedEncephalomyelitis, Autoimmune, ExperimentalEpitopesFemaleHerpes ZosterHerpesvirus 3, HumanHumansInfantInterferon-gammaInterleukin-2Interleukin-4MaleMyelin Basic ProteinT-LymphocytesConceptsAcute disseminated encephalomyelitisMBP-reactive T cell linesCentral nervous systemT cellsIL-4T cell linesDisseminated encephalomyelitisSignificant IFN-gamma secretionMyelin-reactive T cellsIFN-gamma secretionIL-4 secretionTh2 T cellsCell linesAutoimmune diseasesPredominant cytokineNormal subjectsSpontaneous recoveryNervous systemPatientsEncephalomyelitisCytokinesSecretionRecovery phaseCellsSubjects
1996
TCR usage in human and experimental demyelinating disease
Hafler D, Saadeh M, Kuchroo V, Milford E, Steinman L. TCR usage in human and experimental demyelinating disease. Trends In Immunology 1996, 17: 152-159. PMID: 8871344, DOI: 10.1016/0167-5699(96)80611-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsConserved SequenceDemyelinating DiseasesEncephalomyelitis, Autoimmune, ExperimentalHumansMultiple SclerosisReceptors, Antigen, T-Cell, alpha-betaRole of Th1 and Th2 Cells in Neurologic Disorders
Windhagen A, Nicholson LB, Weiner HL, Kuchroo VK, Hafler DA. Role of Th1 and Th2 Cells in Neurologic Disorders. Chemical Immunology And Allergy 1996, 63: 171-186. PMID: 8934837, DOI: 10.1159/000425063.Peer-Reviewed Original ResearchAnimalsDisease Models, AnimalEncephalomyelitis, Autoimmune, ExperimentalHumansMultiple SclerosisTh1 CellsTh2 Cells
1995
Antigen-Specific Immunosuppression: Oral Tolerance for the Treatment of Autoimmune Disease
Hafler DA, Weiner HL. Antigen-Specific Immunosuppression: Oral Tolerance for the Treatment of Autoimmune Disease. Chemical Immunology And Allergy 1995, 60: 126-149. PMID: 7857525, DOI: 10.1159/000423974.Peer-Reviewed Original ResearchAnimalsAntigensAutoimmune DiseasesEncephalomyelitis, Autoimmune, ExperimentalHumansImmune ToleranceImmunosuppression TherapyLymphocyte ActivationMultiple SclerosisT-Lymphocytes
1994
Regulatory T Cell Clones Induced by Oral Tolerance: Suppression of Autoimmune Encephalomyelitis
Chen Y, Kuchroo V, Inobe J, Hafler D, Weiner H. Regulatory T Cell Clones Induced by Oral Tolerance: Suppression of Autoimmune Encephalomyelitis. Science 1994, 265: 1237-1240. PMID: 7520605, DOI: 10.1126/science.7520605.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAmino Acid SequenceAnimalsCD4-Positive T-LymphocytesClone CellsEncephalomyelitis, Autoimmune, ExperimentalEpitopesImmune ToleranceInterleukin-10Interleukin-4Lymph NodesMajor Histocompatibility ComplexMesenteryMiceMolecular Sequence DataMyelin Basic ProteinMyelin ProteinsMyelin Proteolipid ProteinReceptors, Antigen, T-CellTransforming Growth Factor betaConceptsExperimental autoimmune encephalomyelitisMyelin basic proteinT cell clonesAutoimmune encephalomyelitisT cell receptor usageCell-mediated autoimmune diseaseMajor histocompatibility complex restrictionRegulatory T-cell clonesCell clonesMesenteric lymph nodesTh2-like clonesOral antigenOral toleranceEncephalitogenic CD4Lymph nodesPeripheral toleranceInterleukin-10Multiple sclerosisSJL miceAutoimmune diseasesOral administrationT cellsImmune responseInterleukin-4Animal modelsT cell receptor (TCR) usage determines disease susceptibility in experimental autoimmune encephalomyelitis: studies with TCR V beta 8.2 transgenic mice.
Kuchroo VK, Collins M, al-Sabbagh A, Sobel RA, Whitters MJ, Zamvil SS, Dorf ME, Hafler DA, Seidman JG, Weiner HL. T cell receptor (TCR) usage determines disease susceptibility in experimental autoimmune encephalomyelitis: studies with TCR V beta 8.2 transgenic mice. Journal Of Experimental Medicine 1994, 179: 1659-1664. PMID: 8163944, PMCID: PMC2191471, DOI: 10.1084/jem.179.5.1659.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceDisease SusceptibilityDNAEncephalomyelitis, Autoimmune, ExperimentalMiceMice, TransgenicMolecular Sequence DataReceptors, Antigen, T-CellReceptors, Antigen, T-Cell, alpha-betaConceptsExperimental allergic encephalomyelitisMyelin basic proteinAutoimmune diseasesEncephalitogenic epitopeTCR repertoireTCR VProteolipid proteinTransgenic miceT cell receptor usageDiverse T cell repertoireT cell receptor repertoireExperimental autoimmune encephalomyelitisAutoreactive T cellsCell receptor repertoireT cell repertoireT cell clonesAutoimmune encephalomyelitisAllergic encephalomyelitisSJL miceT cellsCell repertoirePLP epitopesReceptor usageReceptor repertoireImmunization
1993
Biological activity of recombinant human myelin basic protein
Oettinger H, Al-Sabbagh A, Jingwu Z, LaSalle J, Weiner H, Hafler D. Biological activity of recombinant human myelin basic protein. Journal Of Neuroimmunology 1993, 44: 157-162. PMID: 7685037, DOI: 10.1016/0165-5728(93)90037-y.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAmino Acid SequenceAnimalsCells, CulturedEncephalomyelitis, Autoimmune, ExperimentalFemaleHumansMiceMolecular Sequence DataMyelin Basic ProteinRecombinant ProteinsT-LymphocytesConceptsRecombinant human myelin basic proteinRecombinant protein bindsRecombinant MBPInducible expression vectorBasic proteinMyelin basic proteinRecombinant protein preparationsProtein bindsHuman myelin basic proteinRecombinant proteinsExpression vectorEscherichia coliProtein preparationsProteinNative MBPE. coliCation exchange chromatographySDS-PAGEBiological reagentsSimilar affinityHuman MBPColiBiological activitySimilar conformationsCell clones
1992
Autoreactive T Cells in Multiple Sclerosis
Zhang J, Weiner H, Hafler D. Autoreactive T Cells in Multiple Sclerosis. International Reviews Of Immunology 1992, 9: 183-201. PMID: 1285060, DOI: 10.3109/08830189209061790.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoantigensAutoimmunityEncephalomyelitis, Autoimmune, ExperimentalHumansLymphocyte ActivationMajor Histocompatibility ComplexMultiple SclerosisMyelin Basic ProteinReceptors, Antigen, T-CellT-LymphocytesConceptsCentral nervous systemMultiple sclerosisInflammatory processT cellsCerebrospinal fluidNervous systemAcute MS plaquesActive inflammatory processAutoreactive T cellsChronic inflammatory diseaseCNS inflammatory processesIL-2 receptorPeripheral nervous systemActivated T cellsNeurologic disabilityNeurological functionMS plaquesSensory deficitsInflammatory diseasesOligoclonal immunoglobulinsPositive macrophagesT lymphocytesWhite matterVisual problemsDemyelination
1991
Antigen‐Driven Peripheral Immune Tolerance
WEINER H, ZHANG Z, KHOURY S, MILLER A, AL‐SABBAGH A, BROD S, LIDER O, HIGGINS P, SOBEL R, NUSSENBLATT R, HAFLER D. Antigen‐Driven Peripheral Immune Tolerance. Annals Of The New York Academy Of Sciences 1991, 636: 227-232. PMID: 1793212, DOI: 10.1111/j.1749-6632.1991.tb33454.x.Peer-Reviewed Original ResearchAdministration, OralAnimalsArthritis, ExperimentalAutoantigensAutoimmune DiseasesEncephalomyelitis, Autoimmune, ExperimentalHumansImmune ToleranceImmunizationOrgan SpecificityUveitisSuppression of experimental autoimmune encephalomyelitis by oral administration of myelin antigens: IV. Suppression of chronic relapsing disease in the lewis rat and strain 13 guinea pig
Brod S, al‐Sabbagh A, Sobel R, Hafler D, Weiner H. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin antigens: IV. Suppression of chronic relapsing disease in the lewis rat and strain 13 guinea pig. Annals Of Neurology 1991, 29: 615-622. PMID: 1716432, DOI: 10.1002/ana.410290608.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAnimalsAutoantigensAutoimmune DiseasesCattleDemyelinating DiseasesEncephalomyelitis, Autoimmune, ExperimentalGuinea PigsHypersensitivity, DelayedImmune ToleranceImmunotherapyMyelin Basic ProteinMyelin ProteinsRatsRats, Inbred LewConceptsExperimental autoimmune encephalomyelitisAutoimmune encephalomyelitisMyelin antigensGuinea pig myelinOral administrationCentral nervous systemLewis ratsMyelin basic proteinAntigen-specific peripheral immune toleranceGuinea pigsMonophasic experimental autoimmune encephalomyelitisDelayed-type hypersensitivity responseGuinea pig myelin basic proteinHuman demyelinating disordersOngoing immune responsePig myelin basic proteinComplete Freund's adjuvantPeripheral immune toleranceExacerbation of diseaseHuman autoimmune diseasesBasic proteinClinical relapseDemyelinating disorderOral toleranceCNS demyelination
1989
MS: a CNS and systematic autoimmune disease
Hafler D, Weiner H. MS: a CNS and systematic autoimmune disease. Trends In Immunology 1989, 10: 104-107. PMID: 2472810, DOI: 10.1016/0167-5699(89)90236-3.Peer-Reviewed Original ResearchMeSH KeywordsCerebrospinal FluidEncephalomyelitis, Autoimmune, ExperimentalEpitopesHumansImmunotherapyMultiple SclerosisT-LymphocytesConceptsPeripheral immune compartmentCentral nervous systemImmune compartmentMultiple sclerosisImmunoregulatory defectsMS patientsAutoimmune diseasesCNS inflammatory responsesTotal lymphoid irradiationProgressive multiple sclerosisT-cell abnormalitiesB cell hyperactivitySystemic lupus erythematosusT cell functionSystematic autoimmune diseaseActivated T cellsLymphoid irradiationDisease activityImmune abnormalitiesSystemic treatmentLupus erythematosusRheumatoid arthritisPeripheral bloodInflammatory diseasesInflammatory response