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 ResearchConceptsMultiple 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 study
2005
High Incidence of Spontaneous Disease in an HLA-DR15 and TCR Transgenic Multiple Sclerosis Model
Ellmerich S, Mycko M, Takacs K, Waldner H, Wahid FN, Boyton RJ, King RH, Smith PA, Amor S, Herlihy AH, Hewitt RE, Jutton M, Price DA, Hafler DA, Kuchroo VK, Altmann DM. High Incidence of Spontaneous Disease in an HLA-DR15 and TCR Transgenic Multiple Sclerosis Model. The Journal Of Immunology 2005, 174: 1938-1946. PMID: 15699121, DOI: 10.4049/jimmunol.174.4.1938.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationCell MovementCentral Nervous SystemDisease Models, AnimalDisease ProgressionDNA-Binding ProteinsEpitopes, T-LymphocyteHLA-DR AntigensHLA-DR Serological SubtypesMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMultiple SclerosisMyelin Basic ProteinParalysisPeptide FragmentsReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsConceptsT cell responsesHLA-DR15Multiple sclerosisDeterminant spreadSpontaneous diseaseCell responsesCD4 T cell recognitionCNS tissue damageHuman multiple sclerosisMultiple sclerosis modelT cell reactivityExperimental allergic encephalomyelitisMyelin oligodendrocyte glycoproteinT cell recognitionMyelin basic proteinAllergic encephalomyelitisMyelin epitopesPeptide immunotherapyAxonal degenerationCell reactivityOligodendrocyte glycoproteinPathogenic roleT cellsHigh incidenceTransgenic mice
2004
PD-1 ligands, negative regulators for activation of naïve, memory, and recently activated human CD4+ T cells
Cai G, Karni A, Oliveira EM, Weiner HL, Hafler DA, Freeman GJ. PD-1 ligands, negative regulators for activation of naïve, memory, and recently activated human CD4+ T cells. Cellular Immunology 2004, 230: 89-98. PMID: 15598424, DOI: 10.1016/j.cellimm.2004.09.004.Peer-Reviewed Original ResearchConceptsPD-1 ligand blockadeT cellsPD-L1Myelin basic proteinPD-L2Human CD4Ex vivo dendritic cellsVivo dendritic cellsPD-1 ligandsPD-1 pathwayPrimary responseActivation of naïveNaive T cellsPD-1Dendritic cellsCytokine productionNormal donorsIFN-gammaSecondary responseCD4BlockadeHigh expressionNegative regulatory pathwaysInduced activationBasic proteinCross-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 ligandsDisease‐related epitope spread in a humanized T cell receptor transgenic model of multiple sclerosis
Ellmerich S, Takacs K, Mycko M, Waldner H, Wahid F, Boyton RJ, Smith PA, Amor S, Baker D, Hafler DA, Kuchroo VK, Altmann DM. Disease‐related epitope spread in a humanized T cell receptor transgenic model of multiple sclerosis. European Journal Of Immunology 2004, 34: 1839-1848. PMID: 15214032, DOI: 10.1002/eji.200324044.Peer-Reviewed Original ResearchConceptsHLA-DR15Multiple sclerosisTransgenic modelT cell receptor transgenic modelHLA class II moleculesHuman T cell clonesInduction of paralysisPoverty of movementHLA class IIT cell clonesClass II moleculesHuman TCR specificMBP 85Specific immunotherapyTCR specificMyelin epitopesT cellsIFN-gammaRodent modelsDiseaseCell clonesEpitopesDisease phenotypeSclerosisImmunization
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 assaysCTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls
Oliveira EM, Bar-Or A, Waliszewska AI, Cai G, Anderson DE, Krieger JI, Hafler DA. CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls. Journal Of Autoimmunity 2003, 20: 71-81. PMID: 12604314, DOI: 10.1016/s0896-8411(02)00106-3.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntigens, CDAntigens, DifferentiationCell DivisionCTLA-4 AntigenHumansMultiple SclerosisMyelin Basic ProteinPolymorphism, GeneticT-LymphocytesConceptsMultiple sclerosisT cellsMyelin basic proteinHealthy controlsMyelin basic protein-reactive T cellsMBP-reactive T cellsPathogenesis of MSPeripheral blood mononuclear cellsCTLA-4 blockadeReactive T cellsBlood mononuclear cellsCo-stimulatory pathwaysNaïve T cellsCo-stimulatory signalsCentral nervous systemCTLA-4 engagementCytokine responsesAutoimmune responseMononuclear cellsInflammatory diseasesB7-CD28Proliferative responseNervous systemPatientsMyelin sheath
2002
Degeneracy, as opposed to specificity, in immunotherapy
Hafler DA. Degeneracy, as opposed to specificity, in immunotherapy. Journal Of Clinical Investigation 2002, 109: 581-584. PMID: 11877465, PMCID: PMC150898, DOI: 10.1172/jci15198.Peer-Reviewed Original Research
2000
Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis
Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. Journal Of Clinical Investigation 2000, 105: 967-976. PMID: 10749576, PMCID: PMC377485, DOI: 10.1172/jci8970.Peer-Reviewed Original ResearchMeSH KeywordsAdultAmino Acid SequenceCell DivisionCells, CulturedCross ReactionsEpitopes, T-LymphocyteFemaleGlatiramer AcetateHumansImmunodominant EpitopesImmunosuppressive AgentsInterferon-gammaInterleukin-5Leukocytes, MononuclearLigandsMaleMiddle AgedMolecular Sequence DataMultiple SclerosisMyelin Basic ProteinMyelin SheathPeptide FragmentsPeptidesTetanus ToxoidTh2 CellsConceptsT cell responsesMultiple sclerosisGlatiramer acetateT cellsAntigen-specific T cell responsesTh2-polarized immune responseCross-reactive T cellsAlters immune functionHuman autoimmune diseasesAcetate inducesCross-reactive responsesT cell receptorT cell linesImmune deviationMost patientsTh2 typeAutoimmune disordersTh2 cytokinesAutoimmune diseasesDaily injectionsIL-13IL-5Th2 cellsHealthy subjectsImmune response
1999
Cross-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 burgdorferiCross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein
Ausubel L, Bieganowska K, Hafler D. Cross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein. Cellular Immunology 1999, 193: 99-107. PMID: 10202117, DOI: 10.1006/cimm.1998.1447.Peer-Reviewed Original ResearchConceptsT cell clonesT cellsSpecific T cell repertoireAutoreactive T cellsTh1-type cytokinesTh2-type cytokinesMultiple sclerosis patientsT cell repertoireAltered peptide ligandT cell receptor alphaPotential beneficial effectsTCR contact residuesMyelin basic proteinDownregulatory cytokinesSclerosis patientsIL-4IL-5Individual patientsReceptor alphaBeneficial effectsClonal expansionCytokinesPeptide ligandsSubstantial proliferationCross reactivity
1998
Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis
Windhagen A, Anderson DE, Carrizosa A, Balashov K, Weiner HL, Hafler DA. Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis. Journal Of Neuroimmunology 1998, 91: 1-9. PMID: 9846813, DOI: 10.1016/s0165-5728(98)00086-1.Peer-Reviewed Original ResearchConceptsMBP-reactive T cellsReactive T cellsChronic progressive multiple sclerosisProgressive multiple sclerosisMultiple sclerosisT cellsCytokine secretionMyelin basic proteinT cell linesNormal controlsMyelin basic protein-reactive T cellsAntigen-specific cytokine secretionMyelin-reactive T cellsNormal individualsShort-term T cell linesAutoreactive T cell linesCP MS patientsIL-12/IL-4/MBP-reactive cellsTh2-type phenotypeRR-MS patientsTh2 cytokine secretionAutoreactive T cellsMore IFN-gammaMyelin 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 phaseCellsSubjectsPulse 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 ProteinsT-Lymphocyte SubsetsTetanus ToxoidThymidineConceptsCD4 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 toleranceAutoantigen recognition by human CD8 T cell clones: enhanced agonist response induced by altered peptide ligands.
Dressel A, Chin JL, Sette A, Gausling R, Höllsberg P, Hafler DA. Autoantigen recognition by human CD8 T cell clones: enhanced agonist response induced by altered peptide ligands. The Journal Of Immunology 1997, 159: 4943-51. PMID: 9366420, DOI: 10.4049/jimmunol.159.10.4943.Peer-Reviewed Original ResearchConceptsT cell clonesCD8 T cell clonesTCR contact residuesHLA-A2Superagonist peptideCell clonesSelf-AgHLA-A2.1 binding motifsHuman autoimmune diseasesAltered peptide ligandMHC class IMyelin peptidesHLA-A2.1Autoimmune diseasesAutoantigen recognitionSecrete cytokinesEffector responsesLow MHCImmune responseAgonist responsesImmunodominant epitopesAgonist peptideAg recognitionContact residuesCytotoxic responseChanges in cytokine secretion induced by altered peptide ligands of myelin basic protein peptide 85-99.
Ausubel LJ, Krieger JI, Hafler DA. Changes in cytokine secretion induced by altered peptide ligands of myelin basic protein peptide 85-99. The Journal Of Immunology 1997, 159: 2502-12. PMID: 9278344, DOI: 10.4049/jimmunol.159.5.2502.Peer-Reviewed Original ResearchAutoimmune DiseasesCell DifferentiationCell LineClone CellsGene Rearrangement, T-LymphocyteHumansImmunodominant EpitopesInterferon-gammaInterleukin-4Interleukin-5Lymphocyte ActivationMultiple SclerosisMyelin Basic ProteinPeptide FragmentsReceptors, Antigen, T-Cell, alpha-betaStructure-Activity RelationshipT-Lymphocyte SubsetsTh1 CellsTh2 CellsWeak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones.
Anderson DE, Ausubel LJ, Krieger J, Höllsberg P, Freeman GJ, Hafler DA. Weak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones. The Journal Of Immunology 1997, 159: 1669-75. PMID: 9257827, DOI: 10.4049/jimmunol.159.4.1669.Peer-Reviewed Original ResearchDirect Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease
Bieganowska K, Ausubel L, Modabber Y, Slovik E, Messersmith W, Hafler D. Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease. Journal Of Experimental Medicine 1997, 185: 1585-1594. PMID: 9151896, PMCID: PMC2196290, DOI: 10.1084/jem.185.9.1585.Peer-Reviewed Original ResearchConceptsAutoreactive T cellsT cellsMultiple sclerosisPersistent T cellsT cell frequenciesHuman autoimmune diseasesSubpopulation of patientsT cell clonesT cell receptorSingle T cellsMyelin basic proteinAutoimmune diseasesAutoantigenic peptidesAntigen stimulationDirect exCell frequencyTCR transcriptsFlow cytometryCell receptorCell clonesBeta chainHigh frequencyCell deathBasic proteinChain transcripts