2024
Checkpoint 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 levelsCheckpointAutoantibodiesBlockadeCancerPancreasDiagnosisLangerhansThe 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 discoveriesImmunotherapy
2023
A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Djureinovic D, Weiss S, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto A, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech S, Bosenberg M, Jilaveanu L, Kluger H. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Molecular Cancer 2023, 22: 182. PMID: 37964379, PMCID: PMC10644655, DOI: 10.1186/s12943-023-01884-x.Peer-Reviewed Original ResearchConceptsStable diseasePartial responseMacrophage populationsThree-drug regimenUnconfirmed partial responsePhase I trialLimited treatment optionsMonocyte/macrophage populationNon-classical monocytesMurine melanoma modelTreatment-related changesResultsThirteen patientsWorse survivalI trialInflammatory tumorPatient populationTreatment optionsImmune cellsDisease progressionMurine studiesPreclinical modelsResistant melanomaAntigen presentationMurine modelCyTOF analysisResponse to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng
Aizenbud L, Schoenfeld D, Caulfield J, Mann J, Austin M, Perdigoto A, Herold K, Kluger H. Response to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng. Journal For ImmunoTherapy Of Cancer 2023, 11: e007397. PMID: 37349129, PMCID: PMC10314693, DOI: 10.1136/jitc-2023-007397.Peer-Reviewed Original ResearchGermline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors
Caulfield J, Aizenbud L, Perdigoto A, Meffre E, Jilaveanu L, Michalek D, Rich S, Aizenbud Y, Adeniran A, Herold K, Austin M, Kluger H. Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors. Journal For ImmunoTherapy Of Cancer 2023, 11: e006570. PMID: 36898736, PMCID: PMC10008335, DOI: 10.1136/jitc-2022-006570.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsInsulin-dependent diabetesImmune checkpoint inhibitorsType 1 diabetesCheckpoint inhibitorsControl patientsSevere immune-related adverse eventsImmunotherapy-treated patientsCheckpoint inhibitor therapyIslet cell destructionPotential predictive biomarkersIslet cell functionWhole-exome sequencingICI exposureAdverse eventsGermline genetic variantsInhibitor therapyPatient selectionTreatment regimensCancer patientsPredictive biomarkersGeneral populationPatientsDiabetesSame drugSpectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor–Induced Hypophysitis
Quandt Z, Kim S, Villanueva-Meyer J, Coupe C, Young A, Kang J, Yazdany J, Schmajuk G, Rush S, Ziv E, Perdigoto A, Herold K, Lechner M, Su M, Tyrrell J, Bluestone J, Anderson M, Masharani U. Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor–Induced Hypophysitis. Journal Of The Endocrine Society 2023, 7: bvad012. PMID: 36860908, PMCID: PMC9969737, DOI: 10.1210/jendso/bvad012.Peer-Reviewed Original ResearchPD-1/PD-L1 inhibitor monotherapyImmune-related adverse eventsPD-L1 inhibitor monotherapyMagnetic resonance imagingCheckpoint inhibitorsInhibitor monotherapyHLA typesPD-1/PD-L1 inhibitorsCTLA-4/PDCTLA-4 inhibitorsImmune checkpoint inhibitorsPD-L1 inhibitorsThyroid function testsInhibitor combination therapyTiming of onsetAdverse eventsMRI changesClinical presentationFunction testsImaging findingsCombination therapyMean ageInhibitor exposureEffect modificationHLA typing
2022
Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes
Perdigoto AL, Deng S, Du KC, Kuchroo M, Burkhardt DB, Tong A, Israel G, Robert ME, Weisberg SP, Kirkiles-Smith N, Stamatouli AM, Kluger HM, Quandt Z, Young A, Yang ML, Mamula MJ, Pober JS, Anderson MS, Krishnaswamy S, Herold KC. Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes. JCI Insight 2022, 7: e156330. PMID: 35925682, PMCID: PMC9536276, DOI: 10.1172/jci.insight.156330.Peer-Reviewed Original ResearchConceptsCheckpoint inhibitorsΒ-cellsPD-1/PD-L1 pathwayT-lymphocyte antigen-4PD-1 blockadePD-L1 pathwayDeath ligand 1NOD mouse modelDevelopment of diabetesHuman β-cellsAutoimmune complicationsNOD miceΒ-cell populationDeath-1Diabetes mellitusImmune infiltratesInflammatory mediatorsPancreatic inflammationPD-L1Induced diabetesLymphocytic infiltrationInflammatory cytokinesAntigen-4Immune cellsT cellsCitrullination of glucokinase is linked to autoimmune diabetes
Yang ML, Horstman S, Gee R, Guyer P, Lam TT, Kanyo J, Perdigoto AL, Speake C, Greenbaum CJ, Callebaut A, Overbergh L, Kibbey RG, Herold KC, James EA, Mamula MJ. Citrullination of glucokinase is linked to autoimmune diabetes. Nature Communications 2022, 13: 1870. PMID: 35388005, PMCID: PMC8986778, DOI: 10.1038/s41467-022-29512-0.Peer-Reviewed Original ResearchConceptsGlucose-stimulated insulin secretionResult of inflammationType 1 diabetesBeta-cell metabolismPancreatic beta cellsAutoimmune diabetesNOD miceAutoreactive CD4Inflammatory cytokinesAutoimmune biomarkersInsulin secretionT cellsBeta cellsType 1InflammationBiologic activityReactive oxygen speciesDiabetesPost-translational modificationsDiabetes biomarkersGlycogen synthesisBiomarkersCitrullinationGlucokinaseOxygen species
2021
Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
Rui J, Deng S, Perdigoto AL, Ponath G, Kursawe R, Lawlor N, Sumida T, Levine-Ritterman M, Stitzel ML, Pitt D, Lu J, Herold KC. Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes. Nature Communications 2021, 12: 5074. PMID: 34417463, PMCID: PMC8379260, DOI: 10.1038/s41467-021-25367-z.Peer-Reviewed Original ResearchConceptsImmune cellsΒ-cellsNOD/SCID recipientsDiabetogenic immune cellsDiabetogenic T cellsBone marrow transplantType 1 diabetesExpression of TET2Human β-cellsIslet infiltratesSCID recipientsMarrow transplantInflammatory pathwaysTransfer of diseaseT cellsInflammatory genesImmune killingPathologic interactionsReduced expressionDiabetesInflammationTET2MiceRecipientsCellsAdverse events induced by immune checkpoint inhibitors
Perdigoto AL, Kluger H, Herold KC. Adverse events induced by immune checkpoint inhibitors. Current Opinion In Immunology 2021, 69: 29-38. PMID: 33640598, PMCID: PMC8122053, DOI: 10.1016/j.coi.2021.02.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityCytotoxicity, ImmunologicDrug-Related Side Effects and Adverse ReactionsGene-Environment InteractionGenetic Predisposition to DiseaseHumansImmune Checkpoint InhibitorsImmunotherapyLymphocyte ActivationNeoplasmsT-LymphocytesConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsAdverse eventsT cellsImmune related adverse eventsEmergence of autoantibodiesRelated adverse eventsAnti-tumor responseAutoreactive T cellsActivated T cellsAutoimmune mechanismsTreatment of cancerAutoimmune diseasesInflammatory responsePredictive valueHost factorsToxic effectsInhibitorsDirect effectOngoing investigationAutoantibodiesCellsAutoimmunityPathogenesisCancerQuantifying the effect of experimental perturbations at single-cell resolution
Burkhardt DB, Stanley JS, Tong A, Perdigoto AL, Gigante SA, Herold KC, Wolf G, Giraldez AJ, van Dijk D, Krishnaswamy S. Quantifying the effect of experimental perturbations at single-cell resolution. Nature Biotechnology 2021, 39: 619-629. PMID: 33558698, PMCID: PMC8122059, DOI: 10.1038/s41587-020-00803-5.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencing datasetsClusters of cellsRNA sequencing datasetsSingle-cell resolutionSingle-cell levelTranscriptomic spaceSequencing datasetsExperimental perturbationsCell populationsGene signatureVertex frequencyDiscrete regionsCellsEffects of perturbationsMultiple conditionsPerturbation responseClustersPopulationPerturbationsLikelihood estimatesGraph signal processingAdverse events induced by immune checkpoint inhibitors.
Perdigoto AL, Kluger H, Herold KC. Accepted and in press at Current Opinion Immunology, special issue Tumor Immunology 2021.Peer-Reviewed Original Research
2020
Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors.
Perdigoto AL, Tran T, Patel N, Clark P, Patell K, Stamatouli AM, Reddy V, Clune J, Herold KC, Robert ME, Kluger HM. Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors. Clinical Oncology Case Reports 2020, 3 PMID: 33778814, PMCID: PMC7993656.Peer-Reviewed Original ResearchCheckpoint inhibitor therapyElective colectomyUlcerative colitisInhibitor therapyMetastatic melanomaImmune-related adverse eventsExcellent tumor responseImmune checkpoint inhibitorsSevere ulcerative colitisActive ulcerative colitisCheckpoint inhibitor immunotherapyCheckpoint inhibitor treatmentInflammatory bowel diseaseEffective treatment optionBenefits of treatmentImmune system activationTumor cell destructionCheckpoint inhibitorsAdvanced malignanciesAdverse eventsSelect patientsBowel diseaseAutoimmune diseasesTreatment optionsTumor response
2019
Checkpoint inhibitor-induced insulin-dependent diabetes: an emerging syndrome
Perdigoto AL, Quandt Z, Anderson M, Herold KC. Checkpoint inhibitor-induced insulin-dependent diabetes: an emerging syndrome. The Lancet Diabetes & Endocrinology 2019, 7: 421-423. PMID: 30885563, DOI: 10.1016/s2213-8587(19)30072-5.Peer-Reviewed Original Research
2018
Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis
Perdigoto AL, Preston-Hurlburt P, Clark P, Long SA, Linsley PS, Harris KM, Gitelman SE, Greenbaum CJ, Gottlieb PA, Hagopian W, Woodwyk A, Dziura J, Herold KC. Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis. Diabetologia 2018, 62: 655-664. PMID: 30569273, PMCID: PMC6402971, DOI: 10.1007/s00125-018-4786-9.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAntibodies, Monoclonal, HumanizedArea Under CurveAutoimmunityCD3 ComplexCD8-Positive T-LymphocytesChildC-PeptideCytokinesDiabetes Mellitus, Type 1FemaleFollow-Up StudiesHumansHypoglycemic AgentsInsulinIslets of LangerhansMaleRandomized Controlled Trials as TopicRemission InductionTreatment OutcomeYoung AdultConceptsC-peptide responseType 1 diabetesMixed meal tolerance testDetectable C-peptideC-peptideInsulin useTolerance testT cellsControl groupNew-onset type 1 diabetesPeripheral blood mononuclear cellsConclusions/interpretationThese findingsAnti-CD3 monoclonal antibodyDaily insulin useBlood mononuclear cellsDiagnosis of diabetesSuccessful immune therapiesOriginal control groupCell death proteinAnergic CD8ResultsFifty-sixImmune therapyInterpretationThese findingsMononuclear cellsCytokine release
2017
Have we pushed the needle for treatment of Type 1 diabetes?
Naushad N, Perdigoto AL, Rui J, Herold KC. Have we pushed the needle for treatment of Type 1 diabetes? Current Opinion In Immunology 2017, 49: 44-50. PMID: 28992525, PMCID: PMC5937133, DOI: 10.1016/j.coi.2017.09.004.Peer-Reviewed Original ResearchPioglitazone and cardiovascular risk reduction
Perdigoto AL, Young LH, Inzucchi SE. Pioglitazone and cardiovascular risk reduction. Cardiovascular Endocrinology & Metabolism 2017, 6: 55-61. PMID: 31646121, PMCID: PMC6768516, DOI: 10.1097/xce.0000000000000110.Peer-Reviewed Original ResearchInsulin Resistance InterventionCV outcomesInsulin resistanceResistance InterventionImpact of thiazolidinedionesCardiovascular risk reductionGlucose-lowering drugsCardiovascular disease riskInsulin-resistant patientsType 2 diabetesCV complicationsMacrovascular eventsCV riskSecondary preventionResistant patientsStroke patientsStroke trialsPathophysiological abnormalitiesAntihyperglycemic agentsInsulin sensitivityDiabetes managementClinical practiceStroke resultsPatientsDisease risk
2010
A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons
Perdigoto AL, Chaudhry N, Barnes GN, Filbin MT, Carter BD. A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons. Molecular And Cellular Neuroscience 2010, 46: 235-244. PMID: 20869442, PMCID: PMC3018674, DOI: 10.1016/j.mcn.2010.09.006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedCerebral CortexCHO CellsCoculture TechniquesCricetinaeCricetulusHEK293 CellsHumansMiceMice, Inbred C57BLMice, KnockoutMyelin-Associated GlycoproteinNeuritesNeuronsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseReceptor, Nerve Growth FactorRho GTP-Binding ProteinsRho-Associated KinasesConceptsCortical neuronsInhibitory effectNeurite outgrowthEffect of MAGP75 neurotrophin receptorPI3K/AKT axisCentral nervous systemPTEN/PI3K/AKT axisAxonal regenerationCorticospinal tractPermanent disabilityNeurotrophin receptorNervous systemAKT axisPhospho-AktNeuronsStriking reductionProcess outgrowthDownstream effector kinasesMyelinInhibitory proteinNovel rolePTENReceptorsNovel pathway
2004
Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155
Madani N, Perdigoto AL, Srinivasan K, Cox JM, Chruma JJ, LaLonde J, Head M, Smith AB, Sodroski JG. Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155. Journal Of Virology 2004, 78: 3742-3752. PMID: 15016894, PMCID: PMC371073, DOI: 10.1128/jvi.78.7.3742-3752.2004.Peer-Reviewed Original ResearchConceptsBMS-806Envelope glycoproteinHuman immunodeficiency virus type 1 (HIV-1) entryGp41 transmembrane envelope glycoproteinGp120 exterior envelope glycoproteinHIV-1 envelope glycoproteinExterior envelope glycoproteinPhe 43 cavityV2 variable loopsCD4-bound conformationTransmembrane envelope glycoproteinHost cell receptorsAntiviral effectCD4 bindingReceptor-binding regionCell receptorReceptor bindingBind gp120Mode of actionGp120Glycoprotein mutantsDrugsNovel inhibitorsGlycoproteinConfer resistance