2024
Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab
Galderisi A, Sims E, Evans-Molina C, Petrelli A, Cuthbertson D, Nathan B, Ismail H, Herold K, Moran A. Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab. Diabetologia 2024, 1-16. PMID: 39560746, DOI: 10.1007/s00125-024-06323-0.Peer-Reviewed Original ResearchProgrammed death-1AUC C-peptideSlow progressorsRapid progressorsInsulin secretionInsulin clearanceC-peptideDisease-free survival ratesT effector memory cellsCD8+ T effector memory cellsNatural historyImpact of immunotherapyPlacebo-treated individualsT memory cellsBaseline insulin secretionBeta cell functionInterpreting clinical trialsLoss of insulin secretionDeath-1Elevated insulin secretionPlacebo-treatedTreatment armsTeplizumabClinical trialsDisposition indexEvolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop.
Greenbaum C, Nepom G, Wood-Heickman L, Wherrett D, DiMeglio L, Herold K, Krischer J. Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop. Diabetes 2024, 73: 1780-1790. PMID: 39167668, PMCID: PMC11493760, DOI: 10.2337/dbi24-0020.Peer-Reviewed Original ResearchConceptsType 1 diabetesClinical trialsType 1 Diabetes TrialNetEtiology of type 1 diabetesImmune Tolerance NetworkFood and Drug AdministrationU.S. Food and Drug AdministrationNational Institute of DiabetesDigestive and Kidney DiseasesMultiple immune pathwaysDisease-modifying therapiesMechanism of actionTherapeutic responsePrognostic markerKidney diseaseDrug AdministrationTrialNetClinical diagnosisImmune pathwaysDiabetesTeplizumabRegulatory approvalClinical carePathophysiologyDiseaseTeplizumab induces persistent changes in the antigen‐specific repertoire in individuals at‐risk for type 1 diabetes
Lledó-Delgado A, Preston-Hurlburt P, Currie S, Clark P, Linsley P, Long S, Liu C, Koroleva G, Martins A, Tsang J, Herold K. Teplizumab induces persistent changes in the antigen‐specific repertoire in individuals at‐risk for type 1 diabetes. Journal Of Clinical Investigation 2024, 134: e177492. PMID: 39137044, PMCID: PMC11405034, DOI: 10.1172/jci177492.Peer-Reviewed Original ResearchCD8+ T cellsAutoreactive T cellsT cellsType 1 diabetesPeripheral blood CD8+ T cellsBlood CD8+ T cellsExpansion of autoreactive T cellsOperational toleranceExpression of CD127Progression of type 1 diabetesAnti-CD3 mAbAntigen-specific repertoireT cell receptorAt-risk patientsAnalysis of study participantsStudy participantsIL7R expressionTeplizumab groupCD8+Placebo groupCD4+Clinical respondersFree intervalTeplizumabReduced expression of genesCheckpoint Inhibitor-Induced Autoimmune Diabetes: An Autoinflammatory Disease.
Quandt Z, Perdigoto A, Anderson M, Herold K. Checkpoint Inhibitor-Induced Autoimmune Diabetes: An Autoinflammatory Disease. Cold Spring Harbor Perspectives In Medicine 2024, a041603. PMID: 39038853, DOI: 10.1101/cshperspect.a041603.Peer-Reviewed Original ResearchAutoimmune diabetesBlockade of programmed cell death protein 1Agents targeting immune checkpointsCell death protein 1Autoimmune side effectsPD-L1Immune checkpointsAutoimmune disease riskClinical findingsAdverse eventsLevels of lipaseSide effectsInflammatory processIslets of LangerhansProtein 1DiabetesDisease riskIncreased levelsCheckpointAutoantibodiesBlockadeCancerPancreasDiagnosisLangerhansReshaping immune cells and the antigen-specific repertoire by anti-CD3 mAb teplizumab in Type 1 diabetes
lledo delgado A, Preston-Hurlburt P, Currie S, Clark P, Herold K. Reshaping immune cells and the antigen-specific repertoire by anti-CD3 mAb teplizumab in Type 1 diabetes. The Journal Of Immunology 2024, 212: 0958_5059-0958_5059. DOI: 10.4049/jimmunol.212.supp.0958.5059.Peer-Reviewed Original ResearchCD8+ T cellsT cellsType 1 diabetesCD8+ T cell exhaustionAutoreactive CD8+ T cellsT cell exhaustionT cell changesCD8+ cellsProgression of type 1 diabetesAnti-CD3 mAbAntigen-specific repertoireAt-risk patientsCD8+CD4+Eomes expressionPeripheral bloodTeplizumabImmune cellsImmune regulationT1D diagnosisCD8Operational toleranceDelay progressionMonthsIndividuals at-riskSingle-cell transcriptomics of CD8 T cells in autoimmune diabetes after anti-CD3 monoclonal antibody treatment
Wu Y, Spurrell M, Deng S, Herold K. Single-cell transcriptomics of CD8 T cells in autoimmune diabetes after anti-CD3 monoclonal antibody treatment. The Journal Of Immunology 2024, 212: 0998_4625-0998_4625. DOI: 10.4049/jimmunol.212.supp.0998.4625.Peer-Reviewed Original ResearchPancreas-draining lymph nodesIslet-infiltrating CD8 T cellsCD8 T cellsPre-diabetic NODAnti-CD3 mAbDiverse TCR repertoireT cellsNOD miceTCR repertoireTCF-1Pre-diabetic NOD miceImmune mediated destructionDiabetic NOD miceMonoclonal antibody treatmentLong-term toleranceExpression of EomesExpression of TCF-1Expression of TOXFragments of mAbsDelay type 1 diabetesType 1 diabetesAnti-CD3Autoimmune diabetesAntibody treatmentLymph nodesEarly Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.
Jacobsen L, Cuthbertson D, Bundy B, Atkinson M, Moore W, Haller M, Russell W, Gitelman S, Herold K, Redondo M, Sims E, Wherrett D, Moran A, Pugliese A, Gottlieb P, Sosenko J, Ismail H. Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials. Diabetes Care 2024, 47: 1048-1055. PMID: 38621411, PMCID: PMC11294635, DOI: 10.2337/dc24-0171.Peer-Reviewed Original ResearchConceptsC-peptide area-under-the-curveArea under the curveC-peptideRecent-onset type 1 diabetesTreatment efficacyEarly-phase clinical trialsC-peptide preservationPrimary end pointB cell functionDetect treatment efficacyType 1 diabetesPost hoc analysisRandomized controlled trialsImmune therapyImmunotherapy trialsMonths posttherapyClinical trialsTreatment effectsEnd pointsMetabolic indicesHoc analysisControlled trialsType 1 diabetes trialsMetabolic endpointsIntervention trialsEvidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes.
Latres E, Greenbaum C, Oyaski M, Dayan C, Colhoun H, Lachin J, Skyler J, Rickels M, Ahmed S, Dutta S, Herold K, Marinac M. Evidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes. Diabetes 2024, 73: 823-833. PMID: 38349844, DOI: 10.2337/dbi23-0012.Peer-Reviewed Original ResearchBeta cell functionType 1 diabetesMeasures of beta cell functionDisease-modifying therapiesC-peptideTrials of disease-modifying therapiesClinical benefitCell functionDestruction of pancreatic beta cellsStimulated C-peptideC-peptide levelsEnd-organ complicationsProspective cohort studyAssociated with protectionEnd-organ complications of diabetesChronic autoimmune diseaseClinically meaningful outcomesClinical outcome measuresComplications of diabetesClinical trials of disease-modifying therapiesBeta cell preservationDemonstration of efficacyPancreatic beta cellsPeripheral bloodAutoimmune diseasesThe immunology of type 1 diabetes
Herold K, Delong T, Perdigoto A, Biru N, Brusko T, Walker L. The immunology of type 1 diabetes. Nature Reviews Immunology 2024, 24: 435-451. PMID: 38308004, PMCID: PMC7616056, DOI: 10.1038/s41577-023-00985-4.Peer-Reviewed Original ResearchType 1 diabetesT cellsDestruction of pancreatic B-cellsImmune-targeted interventionsTarget T cellsPathogenesis of T1DB-cell massPancreatic B-cellsAutoimmune destructionB cellsGlucose dysregulationImmune mechanismsImmune systemNatural historyDisease pathogenesisT1DRegulatory approvalTreatment of individualsDiscovery of insulinPathogenesisDiseaseSeminal discoveriesImmunotherapyPeri-Transplant Inflammation and Long-Term Diabetes Outcomes Were Not Impacted by Either Etanercept or Alpha-1-Antitrypsin Treatment in Islet Autotransplant Recipients
Abdel-Karim T, Hodges J, Herold K, Pruett T, Ramanathan K, Hering B, Dunn T, Kirchner V, Beilman G, Bellin M. Peri-Transplant Inflammation and Long-Term Diabetes Outcomes Were Not Impacted by Either Etanercept or Alpha-1-Antitrypsin Treatment in Islet Autotransplant Recipients. Transplant International 2024, 37: 12320. PMID: 38357216, PMCID: PMC10864605, DOI: 10.3389/ti.2024.12320.Peer-Reviewed Original ResearchConceptsAlpha 1-antitrypsinTolerance testPerioperative periodAlpha-1 antitrypsin treatmentMixed meal tolerance testBenefit of etanerceptMeal tolerance testTrial of etanerceptGlucose tolerance testMonths post-TPIATIntravenous glucose tolerance testIslet autotransplant recipientsLong-term diabetes outcomesSerum A1ATEtanercept groupAdministered etanerceptAutotransplant recipientsDiabetes outcomesInflammatory profileEtanerceptIL-10Endogenous upregulationMCP-1Randomized trialsInflammatory cytokinesComparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals
Sims E, Cuthbertson D, Jacobsen L, Ismail H, Nathan B, Herold K, Redondo M, Sosenko J. Comparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals. The Journal Of Clinical Endocrinology & Metabolism 2024, 109: 2116-2123. PMID: 38267821, PMCID: PMC11244203, DOI: 10.1210/clinem/dgae048.Peer-Reviewed Original ResearchSix-month changesPrevention trialsC-peptidePredicting diabetesMetabolic endpointsPreventive treatment effectsMetabolic measuresEffect of disease-modifying therapiesProportional hazards regressionTreatment effectsResponse to immunotherapyMeasurement of glucoseNatural history studiesPrevention StudyHazards regressionInclusion criteriaDisease-modifying therapiesT1D prevention trialsComparing placeboTreatment armsTeplizumabTrialNet PathwayHigh riskDetect treatment effectsCombined glucose
2020
Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients
Pierce CA, Preston-Hurlburt P, Dai Y, Aschner CB, Cheshenko N, Galen B, Garforth SJ, Herrera NG, Jangra RK, Morano NC, Orner E, Sy S, Chandran K, Dziura J, Almo SC, Ring A, Keller MJ, Herold KC, Herold BC. Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Science Translational Medicine 2020, 12: eabd5487. PMID: 32958614, PMCID: PMC7658796, DOI: 10.1126/scitranslmed.abd5487.Peer-Reviewed Original ResearchConceptsImmune responsePediatric patientsAntibody titersAdult patientsSerum concentrationsT cellsSevere acute respiratory syndrome coronavirus 2IFN-γ serum concentrationsAcute respiratory syndrome coronavirus 2Robust T cell responsesSARS-CoV-2 infectionAntibody-dependent cellular phagocytosisRespiratory syndrome coronavirus 2Frequency of IFNMultisystem inflammatory syndromeT cell responsesCellular immune responsesSyndrome coronavirus 2Adaptive immune responsesAntiviral immune responseTumor necrosis factorMetropolitan hospital systemCoronavirus disease 2019COVID-19Age-dependent factors
2019
An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. New England Journal Of Medicine 2019, 381: 603-613. PMID: 31180194, PMCID: PMC6776880, DOI: 10.1056/nejmoa1902226.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAntibodies, Monoclonal, HumanizedCD3 ComplexChildDiabetes Mellitus, Type 1Disease ProgressionDouble-Blind MethodExanthemaFemaleGlucose Tolerance TestHLA-DR3 AntigenHLA-DR4 AntigenHumansLymphocyte CountLymphopeniaMaleMiddle AgedProportional Hazards ModelsT-LymphocytesYoung AdultConceptsType 1 diabetesClinical type 1 diabetesTeplizumab groupPlacebo groupOral glucose tolerance testInsulin-producing beta cellsDouble-blind trialChronic autoimmune diseaseGlucose tolerance testRelatives of patientsRate of diagnosisHigh-risk participantsTransient lymphopeniaAdverse eventsHazard ratioHLA-DR3HLA-DR4Median timeClinical progressionAutoimmune diseasesExogenous insulinCD3 antibodyT cellsTeplizumabClinical disease
2018
Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors
Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, Lee J, Bluestone JA, Anderson M, Herold KC. Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors. Diabetes 2018, 67: dbi180002. PMID: 29937434, PMCID: PMC6054443, DOI: 10.2337/dbi18-0002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, ImmunologicalAutoimmune DiseasesB7-H1 AntigenDiabetes Mellitus, Type 1Genetic Predisposition to DiseaseGenotypeHLA-DR4 AntigenHumansHypoglycemic AgentsInsulinInsulin SecretionIsoantibodiesKetosisModels, ImmunologicalNeoplasmsPancreasPancreatitisProgrammed Cell Death 1 ReceptorConceptsInsulin-dependent diabetesCheckpoint inhibitorsAdverse eventsHLA-DR4Classic type 1 diabetesPD-L1 checkpoint inhibitorsEvidence of pancreatitisImmune adverse eventsSolid organ cancersType 1 diabetesPeridiagnosis periodPositive autoantibodiesL1 antibodyInsulin-DependentHigh riskPatientsDiabetesCancerInhibitorsKetoacidosisAutoimmuneAutoantibodiesPancreatitisComplicationsSyndrome
2015
β Cell death and dysfunction during type 1 diabetes development in at-risk individuals
Herold KC, Usmani-Brown S, Ghazi T, Lebastchi J, Beam CA, Bellin MD, Ledizet M, Sosenko JM, Krischer JP, Palmer JP. β Cell death and dysfunction during type 1 diabetes development in at-risk individuals. Journal Of Clinical Investigation 2015, 125: 1163-1173. PMID: 25642774, PMCID: PMC4362259, DOI: 10.1172/jci78142.Peer-Reviewed Original ResearchConceptsUnmethylated INS DNAINS DNARisk individualsType 1 diabetes developmentCell killingT1D-associated autoimmunityUnmethylated insulin DNADiagnosis of T1DHigh-risk subjectsAmerican Diabetes AssociationHealthy control subjectsJuvenile Diabetes Research FoundationPrimary pathologic processType 1 diabetesCell deathΒ-cell deathNonprogressor groupPeridiagnosis periodTrialNet PathwayBlood testsDiabetes AssociationDiabetes developmentIslet autotransplantMetabolic decompensationControl subjects
2012
Teplizumab Induces Human Gut-Tropic Regulatory Cells in Humanized Mice and Patients
Waldron-Lynch F, Henegariu O, Deng S, Preston-Hurlburt P, Tooley J, Flavell R, Herold KC. Teplizumab Induces Human Gut-Tropic Regulatory Cells in Humanized Mice and Patients. Science Translational Medicine 2012, 4: 118ra12. PMID: 22277969, PMCID: PMC4131554, DOI: 10.1126/scitranslmed.3003401.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedCD3 ComplexCell MovementDiabetes Mellitus, Type 1Forkhead Transcription FactorsGastrointestinal TractHumansHypoglycemic AgentsInterleukin-10Intestine, SmallL-SelectinMiceMucous MembraneNatalizumabOligonucleotide Array Sequence AnalysisReceptors, CCR6T-Lymphocytes, RegulatoryConceptsHumanized micePeripheral circulationSmall intestineType 1 diabetes mellitusNovel immunologic mechanismIL-10 expressionTreatment of patientsType 1 diabetesSecondary lymph organsHuman immune cellsT cell migrationMechanism of actionGut-tropicImmunologic mechanismsRegulatory cellsDiabetes mellitusImmune therapyInterleukin-10Immune cellsRegulatory cytokinesClinical trialsPreclinical modelsClinical studiesT cellsHuman hematopoietic stem cells