Alfred Bothwell, PhD
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Immunobiology
Primary
Immunobiology
Secondary
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Immunobiology
PO Box 208011, 300 Cedar Street
New Haven, CT 06520-8011
United States
Appointments
Immunobiology
Primary
Immunobiology
Secondary
Titles
Member of HTI and VBT
Contact Info
Immunobiology
PO Box 208011, 300 Cedar Street
New Haven, CT 06520-8011
United States
Appointments
Immunobiology
Primary
Immunobiology
Secondary
Titles
Member of HTI and VBT
Contact Info
Immunobiology
PO Box 208011, 300 Cedar Street
New Haven, CT 06520-8011
United States
About
Titles
Professor Emeritus of Immunobiology
Member of HTI and VBTBiography
Al Bothwell graduated with an A.B. from Washington University in 1971, got a PhD from Yale in Sidney Altman’s lab in 1975 and then did a postdoc with David Baltimore at MIT where he established the genetic basis of the anti-NP idiotypic antibody response. He has been on the Immunobiology faculty at the Yale Medical School since 1982. He continued studies of B cell antibody diversity and memory and then worked on T cell receptor structure/function and signaling. He also developed the molecular genetics of the Ly6 gene family (aka Sca-1/Ly6A and Ly6C). Increasingly his work has shifted to studies of human immunity with development of humanized mouse models of vascular disease/transplantation, type 1 diabetes and cancer. Studies on gut inflammation in a genetic tumor model and Inflammatory Bowel Disease have lead most recently to contributions concerning wnt signaling to infections and asthma. His studies focus on the remarkable immunoregulatory properties of Wnt signaling that is both canonical and non-canonical and involves direct interaction with platelets.This is a basic mechanism for regulating tissue permeability affecting the mobility of lymphocytes and tumor cells.
Appointments
Immunobiology
EmeritusPrimaryImmunobiology
Senior Research ScientistSecondary
Other Departments & Organizations
- Diabetes Research Center
- Fellowship Training
- Human and Translational Immunology Program
- Immunobiology
- Program for Biomedical Ethics
- Rheumatic Diseases Research Core
- Vascular Biology and Therapeutics Program
- WHRY Pilot Project Program Investigators
- Women's Health Research at Yale
- Yale Cancer Center
- Yale Center for Immuno-Oncology
- Yale Ventures
Education & Training
- Postdoctoral Fellow
- MIT (1982)
- Postdoctoral Fellow
- Cold Spring Harbor Laboratory (1976)
- PhD
- Yale University, Biology (1975)
- BA
- Washington University, Biology Dept. (1971)
Research
Overview
The
research goals of the lab are to characterize the development and function of
regulatory T cells and characterize mechanisms that affect autoimmunity,
inflammation, transplantation and recruitment into vascular sites. Both mouse and human responses are
studied in vitro and in vivo which includes the development and use of
humanized mice. In addition, our
experience with synthetic microvessels has lead to a translational project to
revascularize islets to treat type I diabetes.
Specific accomplishments in the last year:
Specific accomplishments in the last year:
- PPARs: Peroxysome proliferated activated receptors (PPARs) represent a group of transcription factors that are critical in regulating glucose and lipid metabolism. Ligands of PPARg inhibit metabolically induced arteriosclerosis and also prevent the development of inflammatory disorders in several experimental mouse models including EAE, asthma, rheumatic arthritis and sepsis. The role of PPARg in graft arteriosclerosis (GA) has not been characterized. We therefore tested the in vivo effects of administration of the endogenously occurring ligand, 15 deoxy-prostaglandin-J2 (15-d-PGJ2), and ciglitazone and pioglitazone on vascular remodeling of human artery induced by alloreactive PBMC and the IFN-g model. The data indicate that 15-d-PGJ2 and pioglitazone significantly inhibit human GA in our in vivo human arterial graft model in immunodeficient mice. These effects appear specific because they are reversed by treatment with an antagonist, GW9662. Preliminary results suggest that it is possible to reverse disease once it is established for 3 weeks in this model.
- Microorgan Islet Grafts: The goal of this project is to bioengineer pancreatic beta cell-containing implants for treatment of diabetes. Casting the islets together with EC in collagen gels effectively revascularizes the islets in SCID/bg mice. Indeed, our pilot data indicate that these human islet-EC microorgans secrete human insulin into the peripheral blood of mice for periods of at least 4 months and demonstrate responsiveness to glucose in glucose tolerance tests. We are characterizing the structure/function properties of these microorgans in detail, including the microvessel structure and the stability of the microvessels with time. During the last year we (with Serge Kobsa and M. Saltzman) are characterizing new nanospheres that have a greater capacity to secrete factors for longer periods of time. We have shown that Hepatocyte Growth Factor (HGF) has significant anti-apoptotic activity on islets in vitro and hope to evaluate this with the new delivery systems in vivo. Inflammation and Colon Cancer: The APC/Min mouse is a highly studied model of intestinal tumorigenesis. During the last year we have shown that APC/Min mice that are deficient in the proinflammatory cytokine IL-17A have a 90% reduction in small intestinal polyps. We hope to define both the source of the IL-17A that is critical as well as the cell type that is the target of this cytokine.
Medical Subject Headings (MeSH)
Biochemistry; Biology; Biomedical Engineering; Immunogenetics
Research at a Glance
Yale Co-Authors
Frequent collaborators of Alfred Bothwell's published research.
Publications Timeline
A big-picture view of Alfred Bothwell's research output by year.
James Leckman, MD, PhD
David G. Schatz, PhD
Hong-Jai Park
Ivana Kawikova
Diane McMahon-Pratt, PhD
Joseph Craft, MD
74Publications
3,962Citations
Publications
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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsRegulatory 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 functionMyeloidDickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation
Chae WJ, Bothwell ALM. Dickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation. Differentiation 2019, 108: 33-39. PMID: 31221431, PMCID: PMC6982462, DOI: 10.1016/j.diff.2019.05.003.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsCell proliferationPro-inflammatory ligandsRole of DKK1Pro-inflammatory roleRepair processPoor disease outcomeOrgan homeostasisTransduction pathwaysCanonical WntCell differentiationTissue repair processMulticellular interactionsOrgan injuryCell typesInflammatory diseasesTissue injuryDisease outcomeImmune responseWntBone diseaseWnt antagonistsPathological inflammationMusculoskeletal diseasesExpression levelsDickkopf1Ripk3-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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsReceptor-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
Canonical and Non-Canonical Wnt Signaling in Immune Cells
Chae WJ, Bothwell ALM. Canonical and Non-Canonical Wnt Signaling in Immune Cells. Trends In Immunology 2018, 39: 830-847. PMID: 30213499, PMCID: PMC7367500, DOI: 10.1016/j.it.2018.08.006.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsRegulation 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 ResearchCitationsMeSH Keywords and ConceptsMeSH 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 rejectionIntranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice
Moon JS, Mun CH, Kim JH, Cho JY, Park SD, Park TY, Shin JS, Ho CC, Park YB, Ghosh S, Bothwell ALM, Lee SW, Lee SK. Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. Kidney International 2018, 93: 1118-1130. PMID: 29409726, DOI: 10.1016/j.kint.2017.11.017.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsMeSH KeywordsActive Transport, Cell NucleusAnimalsAnti-Inflammatory AgentsCell NucleusCellular MicroenvironmentCytokinesDisease Models, AnimalFemaleInflammation MediatorsKidneyLupus NephritisMice, Inbred NZBProtein DomainsRecombinant ProteinsSpleenT-Box Domain ProteinsT-Lymphocytes, Helper-InducerT-Lymphocytes, RegulatoryTranscription, GeneticConceptsLupus-prone miceTranscription modulation domainSystemic lupus erythematosusCell subsetsTh1-mediated autoimmune diseasesNucleus-transducible formNumber of Th1Severity of nephritisT cell subsetsT cell activationProinflammatory microenvironmentTh17 cellsTreg cellsImmunosuppressive cytokinesLupus patientsLupus erythematosusAutoimmune diseasesImmune therapeuticsF1 miceCell activationExcessive expressionMiceTbetMarked increaseMethylprednisoloneTherapeutic 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsRegulatory 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 systemDKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation
Xiao Q, Wu J, Wang WJ, Chen S, Zheng Y, Yu X, Meeth K, Sahraei M, Bothwell ALM, Chen L, Bosenberg M, Chen J, Sexl V, Sun L, Li L, Tang W, Wu D. DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nature Medicine 2018, 24: 262-270. PMID: 29431745, PMCID: PMC5840007, DOI: 10.1038/nm.4496.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAdenomatous Polyposis Coli ProteinBeta CateninCD8-Positive T-LymphocytesCell Line, TumorColorectal NeoplasmsCytotoxicity, ImmunologicGene Expression Regulation, NeoplasticHumansIntercellular Signaling Peptides and ProteinsIntestinal NeoplasmsKiller Cells, NaturalLow Density Lipoprotein Receptor-Related Protein-5MelanomaProgrammed Cell Death 1 ReceptorPTEN PhosphohydrolaseSignal TransductionSTAT5 Transcription FactorTumor Escape
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 ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH 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 functionStat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response
Jayakumar A, Bothwell ALM. Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response. Neoplasia 2017, 19: 595-605. PMID: 28654863, PMCID: PMC5487300, DOI: 10.1016/j.neo.2017.04.006.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAdenomatous Polyposis ColiAnimalsBecaplerminBiomarkersCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell Transformation, NeoplasticCytotoxicity, ImmunologicDisease Models, AnimalDisease ProgressionGene DeletionGene ExpressionInterleukin-4Intestinal MucosaIntestine, SmallMiceMice, KnockoutMyeloid-Derived Suppressor CellsProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins c-sisSTAT6 Transcription FactorConceptsIntestinal tumorigenesisIL-4-induced STAT6Tumor-promoting growth factorsAntitumor T-cell responsesHuman colorectal cancer tissuesMore CD8 cellsPD-1 expressionEpithelial cellsExpansion of MDSCsT cell responsesIL-4 expressionCell proliferationColorectal cancer tissuesPlatelet-derived growth factor-BBIntestinal tumor progressionIntestinal epithelial cellsGrowth factor-BBColon cancer cell linesCD8 responsesPolyp progressionStrong CD8Cancer cell linesCD4 cellsCD8 cellsImmunosuppressive mediators
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Immunobiology
PO Box 208011, 300 Cedar Street
New Haven, CT 06520-8011
United States