2019
Functional Diversity of Myeloid-Derived Suppressor Cells: The Multitasking Hydra of Cancer.
Jayakumar A, Bothwell ALM. Functional Diversity of Myeloid-Derived Suppressor Cells: The Multitasking Hydra of Cancer. The Journal Of Immunology 2019, 203: 1095-1103. PMID: 31427398, PMCID: PMC6703177, DOI: 10.4049/jimmunol.1900500.Peer-Reviewed Original ResearchConceptsRegulatory B cellsRegulatory T cellsT cellsB cellsSuppressor cellsIL-17-producing T cellsAntitumor T cellsB cell functionHost immune responseAbility of MDSCsAttractive immunotherapeutic targetDifferent tumor modelsMDSC functionSuppressive cellsIL-17Tumor cell survivalImmunotherapeutic targetImmunological nicheImmune responseTumor growthTumor modelCancer typesMDSCsCell functionMyeloidRipk3-induced inflammation by I-MDSCs promotes intestinal tumors
Jayakumar A, Bothwell ALM. Ripk3-induced inflammation by I-MDSCs promotes intestinal tumors. Cancer Research 2019, 79: canres.2153.2018. PMID: 30786994, PMCID: PMC7395226, DOI: 10.1158/0008-5472.can-18-2153.Peer-Reviewed Original ResearchConceptsReceptor-interacting protein kinase 3I-MDSCsIntestinal tumorsIntestinal tumor modelTumor modelColorectal cancerT cellsKey inflammatory mechanismsAntitumor T cellsTransplantable tumor modelsPotential therapeutic targetPossible therapeutic interventionsI-MDSCMDSC subsetsInflammatory mechanismsMDSC functionSuppressor cellsTumor sizeInflammatory cytokinesMC38 tumorsCytokine synthesisMonocytic markersTherapeutic targetTumorigenic factorsTherapeutic interventions
2018
Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection
Lim S, Kirkiles-Smith NC, Pober JS, Bothwell ALM, Choi JM. Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection. Biomaterials 2018, 183: 128-138. PMID: 30165256, PMCID: PMC6141312, DOI: 10.1016/j.biomaterials.2018.08.049.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell ProliferationCell-Penetrating PeptidesCTLA-4 AntigenCytokinesEndothelial CellsFemaleGraft RejectionHuman Umbilical Vein Endothelial CellsHumansLymphocyte ActivationMice, Inbred BALB CMice, KnockoutMice, SCIDMicrovesselsReceptors, ChemokineSkinSkin TransplantationT-LymphocytesConceptsT cell responsesHuman T cell responsesT cell infiltrationHuman T cellsT cellsCell responsesGraft rejectionCell infiltrationSCID/beige miceCell-permeable peptideBlood cytokine levelsT cell alloresponsesCD8 T cellsChemokine receptor expressionGranzyme B expressionAlloreactive T cellsSignificant side effectsDouble knockout miceHuman T cell activationBcl-2-transduced human umbilical vein endothelial cellsT cell activationHuman umbilical vein endothelial cellsUmbilical vein endothelial cellsSystemic immunosuppressantsAllograft rejectionTherapeutic Potential of Gene-Modified Regulatory T Cells: From Bench to Bedside
Chae WJ, Bothwell ALM. Therapeutic Potential of Gene-Modified Regulatory T Cells: From Bench to Bedside. Frontiers In Immunology 2018, 9: 303. PMID: 29503652, PMCID: PMC5820299, DOI: 10.3389/fimmu.2018.00303.Peer-Reviewed Original ResearchConceptsRegulatory T cellsInflammatory diseasesT cellsImmune responseEffective antitumor immune responseTherapeutic potentialT cell receptor specificityDysfunction of TregsField of TregsAberrant immune responseAdaptive immune cellsAntitumor immune responseInherent genetic defectsRecognition of antigenTreg functionChronic inflammationImmune cellsTregsImmune reactionsRecipients resultsTherapeutic approachesBasic research findingsOrgan donorsSuppressive functionImmune system
2017
Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis
Chae W, Park J, Henegariu O, Yilmaz S, Hao L, Bothwell ALM. Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis. Immunology 2017, 152: 265-275. PMID: 28556921, PMCID: PMC5588763, DOI: 10.1111/imm.12766.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAutoimmune DiseasesAutoimmunityCell MembraneCell ProliferationCHO CellsColitisColonCricetulusDisease Models, AnimalDNA-Binding ProteinsForkhead Transcription FactorsGenetic Predisposition to DiseaseIntercellular Signaling Peptides and ProteinsLymphocyte ActivationMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein KinasesPhenotypeSelf ToleranceSignal TransductionTime FactorsT-Lymphocytes, RegulatoryTransfectionConceptsRegulatory T cellsTreg cellsDKK-1 expressionAutoimmune colitisDickkopf-1T cellsT cell-mediated toleranceEffector CD4 T cellsCD4 T cellsInduction of toleranceT cell proliferationT cell receptor stimulationNovel TregColitis modelImmunological homeostasisImmunological toleranceFoxp3Receptor stimulationCanonical Wnt pathwayColitisFunctional inhibitionMonoclonal antibodiesDe novo protein synthesisProtein kinase pathwaySuppressor function
2016
Snapshots of CD4 + T cell plasticity in the pathogenesis of allergic asthma
Chae WJ, Bothwell AL. Snapshots of CD4 + T cell plasticity in the pathogenesis of allergic asthma. Journal Of Thoracic Disease 2016, 8: e1010-e1012. PMID: 27747048, PMCID: PMC5059289, DOI: 10.21037/jtd.2016.08.19.Peer-Reviewed Original ResearchThymic stromal lymphopoietinHouse dust miteAllergic asthmaDendritic cellsType 2 inflammatory diseasesT helper type 2 cellsNaïve CD4 T cellsCD4 T cellsHumoral immune responseTh2 effector cellsT cell plasticityType 2 cellsLung epithelial cellsIL-25Lung eosinophiliaIL-33Effector cellsEnvironmental allergensTh2 cytokinesDust miteInflammatory diseasesT cellsImmune responseB cellsEpithelial cellsSex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation
Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM. Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation. International Journal Of Molecular Sciences 2016, 17: 1347. PMID: 27548145, PMCID: PMC5000743, DOI: 10.3390/ijms17081347.Peer-Reviewed Original ResearchConceptsEffector T cell differentiationT cellsT cell differentiationAdaptive immunityFemale T cellsMale T cellsPeroxisome proliferator-activated receptor gammaIL-17 productionDifferentiation of Th1PPARγ agonist pioglitazoneProliferator-activated receptor gammaNaïve T cellsSplenic T cellsMouse splenic T cellsImportant immune regulatorPioglitazone treatmentTfh responsesTh17 cellsAgonist pioglitazoneTreg functionAutoimmune diseasesEstrogen exposureImmune regulatorsCell differentiationTh1Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen
Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM. Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen. Scientific Reports 2016, 6: 28495. PMID: 27335315, PMCID: PMC4917844, DOI: 10.1038/srep28495.Peer-Reviewed Original ResearchConceptsFollicular helper T cell responsesHelper T cell responsesT cell responsesCell responsesTfh cellsT cellsGC responseMale T cellsPeroxisome proliferator-activated receptor gammaTfh cell responsesEffector T cellsPPARγ agonist pioglitazoneProliferator-activated receptor gammaT cell regulationWild-type miceRole of PPARγGerminal center B cellsT cell activationGender-specific differencesTfh responsesAgonist pioglitazoneAutoimmune diseasesMenstrual cycleFemale miceMale miceBlocking MHC class II on human endothelium mitigates acute rejection
Abrahimi P, Qin L, Chang WG, Bothwell AL, Tellides G, Saltzman WM, Pober JS. Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 2016, 1: e85293. PMID: 26900601, PMCID: PMC4756651, DOI: 10.1172/jci.insight.85293.Peer-Reviewed Original ResearchClass II MHC moleculesCytotoxic T lymphocytesII MHC moleculesClass I MHC moleculesMHC moleculesI MHC moleculesEndothelial cellsAcute rejectionT cellsEffector memory T cellsT cell-mediated destructionAcute allograft rejectionCell-mediated destructionGraft endothelial cellsMemory T cellsAlloreactive cytotoxic T lymphocytesExperimental rodent modelsMajor histocompatibility complex moleculesSecondary lymphoid organsMHC class IIClass I major histocompatibility complex moleculesAllogeneic human lymphocytesHistocompatibility complex moleculesPrevents CD4Artery graft
2015
dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis
Lim S, Kim WJ, Kim YH, Lee S, Koo JH, Lee JA, Yoon H, Kim DH, Park HJ, Kim HM, Lee HG, Yun Kim J, Lee JU, Hun Shin J, Kyun Kim L, Doh J, Kim H, Lee SK, Bothwell AL, Suh M, Choi JM. dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. Nature Communications 2015, 6: 8244. PMID: 26372309, PMCID: PMC4579786, DOI: 10.1038/ncomms9244.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisMultiple sclerosisT cellsAutoimmune encephalomyelitisCytotoxic T-lymphocyte antigen-4T-lymphocyte antigen-4T helper 17 (Th17) cellsCNS inflammatory diseasesTherapeutic mouse modelsEffector T cellsHelper 17 cellsT helper 1Blood-brain barrierCentral nervous systemHuman T cellsHelper 1Antigen-4Inflammatory diseasesMouse modelNervous systemCurrent drugsResident cellsBrain tissueEffective agentCell-permeable peptideSpontaneous Intestinal Tumorigenesis in Apc/Min+ Mice Requires Altered T Cell Development with IL‐17A
Chae WJ, Bothwell AL. Spontaneous Intestinal Tumorigenesis in Apc/Min+ Mice Requires Altered T Cell Development with IL‐17A. Journal Of Immunology Research 2015, 2015: 860106. PMID: 26146642, PMCID: PMC4469837, DOI: 10.1155/2015/860106.Peer-Reviewed Original ResearchConceptsApc miceGATA-3 expressionIntestinal tumorigenesisFamilial adenomatous polyposisT cell developmentAdoptive transferIL-17AT cellsFunctional regulatory T cellsNaïve CD4 T cellsFrequency of Foxp3Regulatory T cellsAbility of TregsGene mutationsCD4 T cellsSpontaneous intestinal tumorigenesisWild-type TregsHuman familial adenomatous polyposisApc mouse modelAPC gene mutationsCell developmentAltered T cell developmentInflammatory diseasesTregsLamina propria
2014
The Immunotherapeutic Role of Regulatory T Cells in Leishmania (Viannia) panamensis Infection
Ehrlich A, Castilho TM, Goldsmith-Pestana K, Chae WJ, Bothwell AL, Sparwasser T, McMahon-Pratt D. The Immunotherapeutic Role of Regulatory T Cells in Leishmania (Viannia) panamensis Infection. The Journal Of Immunology 2014, 193: 2961-2970. PMID: 25098291, PMCID: PMC4170189, DOI: 10.4049/jimmunol.1400728.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesAntigen-Antibody ComplexCell ProliferationFemaleImmunotherapy, AdoptiveIndoleamine-Pyrrole 2,3,-DioxygenaseInflammationInterferon-gammaInterleukin-10Interleukin-13Interleukin-17Interleukin-2Leishmania guyanensisLeishmaniasis, MucocutaneousLymphocyte CountMiceMice, Inbred BALB CMice, TransgenicParasite LoadT-Lymphocytes, RegulatoryTransforming Growth Factor betaConceptsRegulatory T cellsPanamensis infectionInflammatory responseT cellsLeishmania parasitesDisease pathologyImmunotherapeutic treatment approachesL. panamensis infectionsLeishmania panamensis infectionPercentage of TregsRIL-2/Th2 inflammatory responseIL-13 levelsParasite loadAlternate treatment strategiesT cell proliferationTreg functionalityDisease exacerbationAdoptive transferIL-17IL-10Naive miceCytokine responsesImmunotherapeutic roleCytokine productionPPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation
Park HJ, Kim DH, Choi JY, Kim WJ, Kim JY, Senejani AG, Hwang SS, Kim LK, Tobiasova Z, Lee GR, Craft J, Bothwell AL, Choi JM. PPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation. PLOS ONE 2014, 9: e99127. PMID: 24921943, PMCID: PMC4055678, DOI: 10.1371/journal.pone.0099127.Peer-Reviewed Original ResearchConceptsFollicular helper T cellsHelper T cellsT cellsGerminal center reactionTfh cellsSheep red blood cell immunizationRed blood cell immunizationCenter reactionPeroxisome proliferator-activated receptor gammaIL-21 expressionProliferator-activated receptor gammaWild-type T cellsType T cellsGerminal center formationGerminal center B cellsT cell activationCell immunizationAutoantibody productionGlomerular inflammationSignature cytokinesAdaptive immunityGerminal centersGlucose metabolismNF-κBB cellsA Humanized Mouse Model of Autoimmune Insulitis
Milam A, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, Herold KC, Bothwell AL. A Humanized Mouse Model of Autoimmune Insulitis. Diabetes 2014, 63: 1712-1724. PMID: 24478396, PMCID: PMC3994947, DOI: 10.2337/db13-1141.Peer-Reviewed Original ResearchConceptsT cellsDiabetic donorsInsulin stainingMouse modelAntigen-pulsed cellsAutoantigen-derived peptidesNOD mouse modelHumanized mouse modelType 1 diabetesPancreatic β-cellsT cell linesHuman T cellsIslet infiltrationAutoimmune diabetesNOD-SCIDAutoimmune insulitisHuman diabetesDestructive infiltrationMouse isletsMechanism of inductionΒ-cellsDiabetesDiabetes researchDisease modelsInsulitis
2011
Reperfusion Injury Intensifies the Adaptive Human T Cell Alloresponse in a Human-Mouse Chimeric Artery Model
Yi T, Fogal B, Hao Z, Tobiasova Z, Wang C, Rao DA, Al-Lamki RS, Kirkiles-Smith NC, Kulkarni S, Bradley JR, Bothwell AL, Sessa WC, Tellides G, Pober JS. Reperfusion Injury Intensifies the Adaptive Human T Cell Alloresponse in a Human-Mouse Chimeric Artery Model. Arteriosclerosis Thrombosis And Vascular Biology 2011, 32: 353-360. PMID: 22053072, PMCID: PMC3262100, DOI: 10.1161/atvbaha.111.239285.Peer-Reviewed Original ResearchConceptsArtery segmentsReperfusion injuryNonimmune injuryHuman artery segmentsHuman-mouse chimeric modelInfrarenal aortic interposition graftsT-cell-mediated injuryMouse hostHuman peripheral blood mononuclear cellsPeripheral blood mononuclear cellsCell-mediated injuryT cell alloresponseBlood mononuclear cellsAdaptive immune responsesAortic interposition graftsImmunodeficient mouse hostsGraft survivalInterposition graftImmunologic rejectionMononuclear cellsT cellsImmune responseMinimal sequelaeChimeric modelInjuryIL-17F deficiency inhibits small intestinal tumorigenesis in ApcMin/+ mice
Chae WJ, Bothwell AL. IL-17F deficiency inhibits small intestinal tumorigenesis in ApcMin/+ mice. Biochemical And Biophysical Research Communications 2011, 414: 31-36. PMID: 21939640, DOI: 10.1016/j.bbrc.2011.09.016.Peer-Reviewed Original ResearchConceptsIL-17FSpontaneous intestinal tumorigenesisIntestinal tumorigenesisLamina propriaCD4 T cellsImmune cell infiltrationCOX-2 expressionSmall intestinal tumorigenesisIL-17IL-17AIL-17A.IL-17F.Thymic atrophyIL-1βCell infiltrationT cellsGut homeostasisSmall intestineMiceSignificant decreaseC expressionTumorigenesisPropriaIntestineAblationPeroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells
Tobiasova Z, Zhang L, Yi T, Qin L, Manes TD, Kulkarni S, Lorber MI, Rodriguez FC, Choi JM, Tellides G, Pober JS, Kawikova I, Bothwell AL. Peroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells. Circulation 2011, 124: 196-205. PMID: 21690493, PMCID: PMC3347886, DOI: 10.1161/circulationaha.110.015396.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnilidesAnimalsArteriesCell MovementCell ProliferationCytokinesGraft RejectionHumansHypoglycemic AgentsImmunologic MemoryIsoantigensMiceMice, SCIDPioglitazonePPAR gammaProstaglandin D2SuperantigensThiazolidinedionesT-LymphocytesTransplantation, HeterologousTransplantation, HomologousConceptsT cell responsesMemory T cellsVascular graft rejectionT cellsPPARγ agonistsVascular rejectionGraft rejectionAllogeneic human peripheral blood mononuclear cellsHuman memory T-cell responsesHuman T cell responsesMemory T cell responsesHuman peripheral blood mononuclear cellsTranscription factor peroxisome proliferator-activated receptorPeripheral blood mononuclear cellsChronic graft lossPeroxisome proliferator-activated receptorT-cell infiltratesAllogeneic T cellsAlloreactive T cellsBlood mononuclear cellsAlloantigen-induced proliferationVascular cell activationHuman arteriesProliferator-activated receptorEffects of PPARγ
2010
Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation
Choi JM, Shin JH, Sohn MH, Harding MJ, Park JH, Tobiasova Z, Kim DY, Maher SE, Chae WJ, Park SH, Lee CG, Lee SK, Bothwell AL. Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 18575-18580. PMID: 20937878, PMCID: PMC2972952, DOI: 10.1073/pnas.1000400107.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAsthmaAutoimmune DiseasesCell Membrane PermeabilityDisease Models, AnimalFemaleForkhead Transcription FactorsHumansInflammatory Bowel DiseasesLymphocyte ActivationMaleMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, Mutant StrainsRecombinant Fusion ProteinsT-Lymphocytes, RegulatoryConceptsAllergic airway inflammationT cellsAirway inflammationAllergic diseasesFOXP3 proteinOvalbumin-induced allergic airway inflammationWild-type CD4 T cellsAllergic disease modelsDevelopment of colitisInflammatory bowel diseaseRegulatory T cellsCD4 T cellsInflammatory immune responseT cell activationFoxP3 transductionBowel diseaseScurfy miceTreg functionAutoimmune diseasesAutoimmune symptomsIntranasal deliveryTherapeutic effectImmune responseSystemic deliveryClinical potentialAblation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis
Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 5540-5544. PMID: 20212110, PMCID: PMC2851824, DOI: 10.1073/pnas.0912675107.Peer-Reviewed Original ResearchConceptsCD4 T cellsSpontaneous intestinal tumorigenesisIL-17AT cellsIntestinal tumorigenesisRegulatory T cell-mediated suppressionEffector CD4 T cellsT cell-mediated suppressionEndogenous IL-17ACell-mediated suppressionInfiltration of lymphocytesIntestinal epithelial cellsHyperproliferative potentialImmunological abnormalitiesAdoptive transferIL-10Proinflammatory mediatorsThymic atrophyInflammatory cytokinesImmunodeficient miceIntestinal architectureHeterozygote mutationsAltered functionMiceTumor development
2008
Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis
Choi JM, Kim SH, Shin JH, Gibson T, Yoon BS, Lee DH, Lee SK, Bothwell AL, Lim JS, Lee SK. Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2008, 105: 19875-19880. PMID: 19066215, PMCID: PMC2604944, DOI: 10.1073/pnas.0805198105.Peer-Reviewed Original ResearchConceptsCollagen-induced arthritisT cell activationCTLA-4Human umbilical vein endothelial cellsCell activationInflammatory cytokine productionErosion of cartilageCytoplasmic domainEffective therapeutic approachActivated T cellsUmbilical vein endothelial cellsCell-permeable formT cell receptor-proximal signalingVein endothelial cellsAntibody levelsRheumatoid arthritisAutoimmune diseasesCytokine productionHuman CTLT cellsTherapeutic approachesCell-permeable recombinant proteinArthritisTransdermal administrationMouse T cell activation