2023
Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity
Shinoda K, Li R, Rezk A, Mexhitaj I, Patterson K, Kakara M, Zuroff L, Bennett J, von Büdingen H, Carruthers R, Edwards K, Fallis R, Giacomini P, Greenberg B, Hafler D, Ionete C, Kaunzner U, Lock C, Longbrake E, Pardo G, Piehl F, Weber M, Ziemssen T, Jacobs D, Gelfand J, Cross A, Cameron B, Musch B, Winger R, Jia X, Harp C, Herman A, Bar-Or A. Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2207291120. PMID: 36634138, PMCID: PMC9934304, DOI: 10.1073/pnas.2207291120.Peer-Reviewed Original ResearchConceptsEarly disease activityDisease activityCD8 T cellsT cellsCD20 therapyPeripheral blood mononuclear cellsCellular immune profilesNew disease activityMS disease activityT cell poolMultiple sclerosis patientsAnti-inflammatory profileBlood mononuclear cellsTreatment-associated changesMultiparametric flow cytometryCentral nervous systemFurther dosingRepeat infusionsImmune profileMS patientsSclerosis patientsValidation cohortMononuclear cellsRelapse developmentImmune cascade
2019
CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome
Choileáin SN, Kleinewietfeld M, Raddassi K, Hafler DA, Ruff WE, Longbrake EE. CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome. Journal Of Translational Autoimmunity 2019, 3: 100032. PMID: 32743517, PMCID: PMC7388357, DOI: 10.1016/j.jtauto.2019.100032.Peer-Reviewed Original ResearchInflammatory T cell subsetsCentral nervous systemT cell subsetsMultiple sclerosisT cellsGut microbiomeCell subsetsCNS-reactive T cellsRelapsing-remitting MS patientsGrey matter inflammationGut-immune axisExpression of CXCR3CD8 T cellsAltered gut microbiomeAutoreactive T cellsMultiple sclerosis correlateGut microbiome compositionInflammatory subsetMS pathogenesisMS patientsTh1 phenotypeAxonal degenerationAutoimmune diseasesCascade of eventsDisease onset
2016
AKT isoforms modulate Th1‐like Treg generation and function in human autoimmune disease
Kitz A, de Marcken M, Gautron AS, Mitrovic M, Hafler DA, Dominguez-Villar M. AKT isoforms modulate Th1‐like Treg generation and function in human autoimmune disease. EMBO Reports 2016, 17: 1169-1183. PMID: 27312110, PMCID: PMC4967959, DOI: 10.15252/embr.201541905.Peer-Reviewed Original ResearchMeSH KeywordsAutoimmune DiseasesBiomarkersCell DifferentiationCytokinesForkhead Transcription FactorsGene Expression ProfilingGene SilencingHumansImmunomodulationInterferon-gammaPhenotypePhosphatidylinositol 3-KinasesProtein IsoformsProto-Oncogene Proteins c-aktSignal TransductionT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryTranscriptomeConceptsAutoimmune diseasesIFNγ secretionHuman TregsGenome-wide gene expression approachUntreated relapsing-remitting MS patientsRelapsing-remitting MS patientsImmune suppressive functionHuman autoimmune diseasesT helper 1Inflammatory cytokines IFNγTreg suppressor functionNovel treatment paradigmEffector phenotypeMS patientsTreg generationCytokines IFNγHelper 1Multiple sclerosisTreatment paradigmSuppressive functionTregsVivo modelDiseaseSecretionSuppressor function
2013
Regulatory T Cells in MS
Gawlik B, Hafler D. Regulatory T Cells in MS. 2013, 27-47. DOI: 10.1007/978-1-4614-7953-6_2.Peer-Reviewed Original ResearchRegulatory T cellsAutoreactive T cellsT cellsCentral nervous systemMultiple sclerosisTreg cellsHealthy individualsPathogenic autoreactive T cellsMultifocal demyelinating diseaseDemyelinating diseaseCNS lesionsMS patientsAutoimmune responseAutoimmune diseasesPeripheral bloodImmune homeostasisImmune responseNervous systemSusceptible individualsProgressive neurodegenerationDiseaseKey regulatorCellsIndividualsHigher number
2008
Multiple Sclerosis and Regulatory T Cells
Costantino CM, Baecher-Allan C, Hafler DA. Multiple Sclerosis and Regulatory T Cells. Journal Of Clinical Immunology 2008, 28: 697-706. PMID: 18763026, PMCID: PMC2752287, DOI: 10.1007/s10875-008-9236-x.Peer-Reviewed Original ResearchConceptsRegulatory T cellsCentral nervous systemAutoreactive T cellsT cellsAntigen-specific Treg cellsAutoreactive effector T cellsAutoimmune tissue damageFrequency of TregsOrgan-specific autoimmunityEffector T cellsReactive T cellsBlood-brain barrierPathology of MSIntroductionMultiple sclerosisTreg cellsMS patientsPeripheral toleranceChronic inflammationMultiple sclerosisImmune disordersNew therapiesHealthy individualsNervous systemTissue damageDisease modelsMultiple Sclerosis and Regulatory T Cells
Hutton J, Baecher-Allan C, Hafler D. Multiple Sclerosis and Regulatory T Cells. 2008, 265-277. DOI: 10.1007/978-0-387-77909-6_13.Peer-Reviewed Original ResearchRegulatory T cellsAutoreactive T cellsMultiple sclerosisT cellsAntigen-specific Treg cellsImmunopathology of MSCentral nervous system white matterAutoimmune tissue damageFrequency of TregsNervous system white matterOrgan-specific autoimmunityEffector T cellsReactive T cellsImmunosuppressive therapyTreg cellsAutoimmune processMS patientsPeripheral toleranceSpecific autoimmunityImmune disordersNew therapiesHealthy individualsB cellsWhite matterTissue damage
2006
Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response
Karni A, Abraham M, Monsonego A, Cai G, Freeman GJ, Hafler D, Khoury SJ, Weiner HL. Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response. The Journal Of Immunology 2006, 177: 4196-4202. PMID: 16951385, DOI: 10.4049/jimmunol.177.6.4196.Peer-Reviewed Original ResearchConceptsMyeloid dendritic cellsDendritic cellsMultiple sclerosisInnate immune systemRR-MSImmune responseImmune systemT cell-mediated autoimmune diseaseSecondary progressive multiple sclerosisCell-mediated autoimmune diseaseStages of MSIncreased percentageProgressive phaseNeuronal degenerative changesSecondary progressive phaseSP-MS patientsProgressive multiple sclerosisProinflammatory immune responsePrimary immune responseNaive T cellsImmunologic basisTh1 responseClinical patternMS patientsPD-L1
2005
Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein
O’Connor K, Appel H, Bregoli L, Call ME, Catz I, Chan JA, Moore NH, Warren KG, Wong SJ, Hafler DA, Wucherpfennig KW. Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein. The Journal Of Immunology 2005, 175: 1974-1982. PMID: 16034142, PMCID: PMC4515951, DOI: 10.4049/jimmunol.175.3.1974.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAutoantibodiesBinding Sites, AntibodyCentral Nervous SystemDemyelinating Autoimmune Diseases, CNSFemaleFluoroimmunoassayHumansMaleMolecular Sequence DataMultiple SclerosisMyelin ProteinsMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinRadioimmunoassaySolutionsConceptsMyelin oligodendrocyte glycoproteinMultiple sclerosisCNS diseaseOligodendrocyte glycoproteinCNS tissueChronic inflammatory CNS diseasesAutoantibody-mediated pathologyInflammatory CNS diseasesCentral nervous system tissueInflammatory CNS diseaseCases of encephalitisHigh-affinity autoantibodiesCases of subacuteNervous system tissueCNS parenchymaMOG autoantibodiesMS patientsOligodendrocyte lossMOG-AbCNS diseasesAutoantibodiesCerebrospinal fluidMOG proteinPostmortem casesControl tissues
2003
Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions
O'Connor KC, Chitnis T, Griffin DE, Piyasirisilp S, Bar-Or A, Khoury S, Wucherpfennig KW, Hafler DA. Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. Journal Of Neuroimmunology 2003, 136: 140-148. PMID: 12620653, DOI: 10.1016/s0165-5728(03)00002-x.Peer-Reviewed Original ResearchConceptsMyelin basic proteinMultiple sclerosisCerebrospinal fluidSoluble myelin basic proteinSemple rabies vaccinePresence of autoantibodiesMultiple sclerosis patientsSera of patientsFraction of patientsAnti-MBP antibodiesHigh-affinity autoantibodiesBasic proteinMBP autoantibodiesRelevant autoantibodiesMS patientsSclerosis patientsAutoimmune diseasesHumoral responseRabies vaccineAutoantibodiesPatientsImmunodominant antigensSerumDiseaseSolid-phase assays
2001
In vitro evidence that immunuaffinity-purified MOG contains immunogenic quantities of contaminating mouse IgG; techniques for producing Ig-free MOG
Ohashi T, Yukitake M, Slavin A, Krieger J, Hafler D. In vitro evidence that immunuaffinity-purified MOG contains immunogenic quantities of contaminating mouse IgG; techniques for producing Ig-free MOG. Journal Of Neuroimmunology 2001, 118: 194-202. PMID: 11498254, DOI: 10.1016/s0165-5728(01)00321-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalAntibody SpecificityBlotting, WesternCell LineClone CellsCytokinesElectrophoresis, Polyacrylamide GelEnzyme-Linked Immunosorbent AssayFlow CytometryHumansImmunoglobulin GImmunophenotypingImmunosorbent TechniquesLymphocyte ActivationMiceMultiple SclerosisMyelin ProteinsMyelin SheathMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinSensitivity and SpecificityT-Lymphocytes
1999
Treatment of progressive multiple sclerosis with pulse cyclophosphamidel methylprednisolone: Response to therapy is linked to the duration of progressive disease
Hohol M, Olek M, Orav E, Stazzone L, Hafler D, Khoury S, Dawson D, Weiner H. Treatment of progressive multiple sclerosis with pulse cyclophosphamidel methylprednisolone: Response to therapy is linked to the duration of progressive disease. Multiple Sclerosis Journal 1999, 5: 403-409. PMID: 10618696, DOI: 10.1177/135245859900500i606.Peer-Reviewed Original ResearchConceptsProgressive multiple sclerosisDuration of progressionMultiple sclerosisProgressive diseaseSecondary progressive multiple sclerosisDuration of MSPrimary progressive patientsProgressive MS patientsPositive clinical responseOpen-label fashionClinical outcome measuresStart of treatmentOnset of diseaseMethylprednisolone therapySecondary progressiveImmunomodulatory treatmentImmunosuppressive therapyProgressive patientsClinical responsePatient characteristicsMS patientsImmunosuppressive agentsAutoimmune diseasesLabel fashionEDSS changeMolecular pathogenesis of multiple sclerosis
Bar-Or A, Oliveira E, Anderson D, Hafler D. Molecular pathogenesis of multiple sclerosis. Journal Of Neuroimmunology 1999, 100: 252-259. PMID: 10695735, DOI: 10.1016/s0165-5728(99)00193-9.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsMyelin-reactive T cellsCentral nervous system white matterB7 costimulatory pathwayNervous system white matterDifferential activation statesMacrophage infiltratesMS patientsAxonal injuryNeurological functionProinflammatory cellsProinflammatory cytokinesCostimulatory pathwayInflammatory diseasesMS lesionsMolecular pathogenesisWhite matterMolecular mimicryMatrix metalloproteinasesNormal individualsAdhesion moleculesSelective expressionSclerosisActivation state
1998
Pulse Cyclophosphamide Plus Methylprednisolone Induces Myelin-Antigen-Specific IL-4-Secreting T Cells in Multiple Sclerosis Patients
Takashima H, Smith D, Fukaura H, Khoury S, Hafler D, Weiner H. Pulse Cyclophosphamide Plus Methylprednisolone Induces Myelin-Antigen-Specific IL-4-Secreting T Cells in Multiple Sclerosis Patients. Clinical Immunology 1998, 88: 28-34. PMID: 9683547, DOI: 10.1006/clin.1998.4558.Peer-Reviewed Original ResearchConceptsIL-4-secreting T cellsUntreated MS patientsProgressive MS patientsT cell linesMS patientsIL-4 secretionMyelin basic proteinT cellsMultiple sclerosisMyelin antigensTetanus toxoidTh1-type autoimmune diseaseShort-term T cell linesCell linesPulse cyclophosphamide therapyTh2-type responseIL-4 productionMultiple sclerosis patientsIFN-gamma productionProteolipid proteinImmune deviationPulse cyclophosphamideCyclophosphamide therapySclerosis patientsAutoimmune diseasesExpansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation.
Scholz C, Patton K, Anderson D, Freeman G, Hafler D. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. The Journal Of Immunology 1998, 160: 1532-8. PMID: 9570577, DOI: 10.4049/jimmunol.160.3.1532.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAntigens, CDAntigens, DifferentiationAutoantigensB7-1 AntigenB7-2 AntigenClone CellsCTLA-4 AntigenEpitopes, T-LymphocyteHumansImmunoconjugatesImmunoglobulin Fc FragmentsImmunosuppressive AgentsInterleukin-4Lymphocyte ActivationMembrane GlycoproteinsMultiple SclerosisMyelin Basic ProteinRecombinant Fusion ProteinsTetanus ToxoidThymidineT-Lymphocyte SubsetsConceptsCD4 T cellsMultiple sclerosisT cellsB7-1Myelin basic proteinPathogenesis of MSMyelin-reactive T cellsPeripheral blood T cellsB7-2 engagementAutoreactive T cellsBlood T cellsAbsence of costimulationCentral nervous systemAntigen-specific signalT cell activationMS patientsB7 costimulationInflammatory diseasesTetanus toxoidB7-2Normal controlsNormal subjectsCostimulatory signalsNervous systemCell activation
1997
Oral Administration of Myelin Induces Antigen‐specific TGF‐β1 Secreting T Cells in Patients with Multiple Sclerosisa
HAFLER D, KENT S, PIETRUSEWICZ M, KHOURY S, WEINER H, FUKAURA H. Oral Administration of Myelin Induces Antigen‐specific TGF‐β1 Secreting T Cells in Patients with Multiple Sclerosisa. Annals Of The New York Academy Of Sciences 1997, 835: 120-131. PMID: 9616767, DOI: 10.1111/j.1749-6632.1997.tb48623.x.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsAutoimmune diseasesOral administrationT cell linesNon-treated MS patientsPLP-reactive T cellsTh1-type autoimmune diseaseShort-term T cell linesCell-mediated autoimmune diseaseOriginal T cell cloneSystemic immune toleranceExperimental autoimmune diseasesNon-treated patientsRegulatory T cellsRelapsing-remitting patientsIFN-gamma secretionT cell clonesCell linesMultiple sclerosisAOral tolerizationOral toleranceMS patientsAutoimmune cascadeImmune toleranceImmune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin‐4 production and associated eosinophilia
Smith D, Balashov K, Hafler D, Khoury S, Weiner H. Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin‐4 production and associated eosinophilia. Annals Of Neurology 1997, 42: 313-318. PMID: 9307252, DOI: 10.1002/ana.410420307.Peer-Reviewed Original ResearchConceptsMonthly intravenous methylprednisolonePulse cyclophosphamide therapyMultiple sclerosisImmune deviationIL-4Cyclophosphamide therapyIFN-beta1bMS patientsHealthy controlsTh1-type cell-mediated autoimmune diseaseCell-mediated autoimmune diseaseMethotrexate-treated patientsT-cell interferonUntreated MS patientsUntreated multiple sclerosisPeripheral blood eosinophiliaProgressive MS patientsTh2-type responseCyclophosphamide-treated patientsIL-10 productionInterleukin-4 productionMinimal IL-4Intravenous cyclophosphamideIntravenous methylprednisoloneBlood eosinophiliaIncreased interleukin 12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand
Balashov K, Smith D, Khoury S, Hafler D, Weiner H. Increased interleukin 12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 599-603. PMID: 9012830, PMCID: PMC19559, DOI: 10.1073/pnas.94.2.599.Peer-Reviewed Original ResearchConceptsIL-12 secretionIFN-gamma secretionMS patientsMultiple sclerosisT cellsIL-12Anti-CD40 ligand antibodyTh1-type immune activationCell-mediated autoimmune diseaseProgressive MS patientsProgressive multiple sclerosisIFN-gamma administrationRelapsing-remitting patientsExacerbation of diseaseInterleukin-12 productionChronic inflammatory diseaseCD40 ligand expressionCentral nervous systemActivated T cellsImmune interventionImmune activationAutoimmune diseasesInterleukin-12Inflammatory diseasesCD40 ligand
1996
Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients.
Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. Journal Of Clinical Investigation 1996, 98: 70-77. PMID: 8690806, PMCID: PMC507402, DOI: 10.1172/jci118779.Peer-Reviewed Original ResearchConceptsMyelin basic proteinT cellsOral administrationAutoimmune diseasesTetanus toxoidT cell linesMS patientsMultiple sclerosisProteolipid proteinFrequency of MBPNon-treated MS patientsPLP-reactive T cellsTh1-type autoimmune diseaseShort-term T cell linesCell-mediated autoimmune diseaseRelapsing-remitting MS patientsOriginal T cell cloneSpecific IFN-gammaSystemic immune toleranceExperimental autoimmune diseasesRegulatory T cellsReactive T cellsIFN-gamma secretionMultiple sclerosis patientsT cell clonesAntigen‐specific TGF‐β1 Secretion with Bovine Myelin Oral Tolerization in Multiple Sclerosis
FUKAURA H, KENT S, PIETRUSEWICZ M, KHOURY S, WEINER H, HAFLER D. Antigen‐specific TGF‐β1 Secretion with Bovine Myelin Oral Tolerization in Multiple Sclerosis. Annals Of The New York Academy Of Sciences 1996, 778: 251-257. PMID: 8610978, DOI: 10.1111/j.1749-6632.1996.tb21133.x.Peer-Reviewed Original ResearchConceptsRelapsing-remitting MS patientsHuman autoimmune diseasesOral tolerizationMultiple sclerosisAutoimmune diseasesT cell linesMS patientsCytokine secretionT cellsAutoreactive T-cell populationsAutoreactive T cellsT cell populationsT-cell fractionCNS white matterFed patientsIL-4Inflammatory responseΒ1 secretionIFN-gammaTolerizationWhite matterPatientsSclerosisBovine myelinSecretion
1995
Correlation of Magnetic Resonance Imaging With Immune and Clinical Measures in 45 MS Patients Receiving 20 to 24 MRI Scans Each Over a 1 ‐Year Period
Weiner H, Guttman C, Khoury S, Hohol M, Hafler D, Orav E, Hsu L, Ahn S, Kikinis R, Jolesz F. Correlation of Magnetic Resonance Imaging With Immune and Clinical Measures in 45 MS Patients Receiving 20 to 24 MRI Scans Each Over a 1 ‐Year Period. Neurology 1995, 45: 1416-1416. DOI: 10.1212/wnl.45.7.1416.Peer-Reviewed Original Research