Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 21

Publication Record

Connections

Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34(+) cells of juvenile myelomonocytic leukemia.
Nakazawa Y, Matsuda K, Kurata T, Sueki A, Tanaka M, Sakashita K, Imai C, Wilson MH, Koike K
(2016) J Hematol Oncol 9: 27
MeSH Terms: Antigens, CD34, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Coculture Techniques, Flow Cytometry, Humans, Immunotherapy, Adoptive, K562 Cells, Leukemia, Myelomonocytic, Juvenile, Ligands, Mutation, Receptors, Antigen, T-Cell, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Recombinant Fusion Proteins, Stem Cell Factor, T-Lymphocytes, Thrombopoietin
Show Abstract · Added September 11, 2017
BACKGROUND - Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML.
METHODS - We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34(+) cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34(+) cells.
RESULTS - GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34(+) cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34(+) cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34(+) cell proliferation, particularly CD34(+)CD38(-) cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34(+) cell colony growth.
CONCLUSIONS - Ligand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells.
Parekh VV, Wu L, Olivares-Villagómez D, Wilson KT, Van Kaer L
(2013) J Immunol 190: 1948-60
MeSH Terms: Adoptive Transfer, Animals, Antigen Presentation, Autoimmunity, Cell Communication, Cell Movement, Cell Proliferation, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Female, Galactosylceramides, Granulocyte-Macrophage Colony-Stimulating Factor, Interferon-gamma, Interleukin-4, Mice, Mice, Transgenic, Myeloid Cells, Natural Killer T-Cells, Nitric Oxide Synthase Type II, Spleen, Transplantation Chimera, Whole-Body Irradiation
Show Abstract · Added March 5, 2014
Invariant NKT (iNKT) cells are a subset of T lymphocytes that recognize glycolipid Ags presented by the MHC class I-related protein CD1d. Activation of iNKT cells with glycolipid Ags, such as the marine sponge-derived reagent α-galactosylceramide (α-GalCer), results in the rapid production of a variety of cytokines and activation of many other immune cell types. These immunomodulatory properties of iNKT cells have been exploited for the development of immunotherapies against a variety of autoimmune and inflammatory diseases, but mechanisms by which activated iNKT cells confer disease protection have remained incompletely understood. In this study, we demonstrate that glycolipid-activated iNKT cells cooperate with myeloid-derived suppressor cells (MDSCs) in protecting mice against the development of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis. We show that α-GalCer induced the expansion and immunosuppressive activities of MDSCs in the spleen of mice induced for development of EAE. Disease protection in these animals also correlated with recruitment of MDSCs to the CNS. Depletion of MDSCs abrogated the protective effects of α-GalCer against EAE and, conversely, adoptive transfer of MDSCs from α-GalCer-treated mice ameliorated passive EAE induced in recipient animals. The cytokines GM-CSF, IL-4, and IFN-γ, produced by activated iNKT cells, and inducible NO synthase, arginase-1, and IL-10 produced by MDSCs, contributed to these effects. Our findings have revealed cooperative immunosuppressive interactions between iNKT cells and MDSCs that might be exploited for the development of improved immunotherapies for multiple sclerosis and other autoimmune and inflammatory diseases.
0 Communities
4 Members
0 Resources
22 MeSH Terms
Macrophage dectin-1 expression is controlled by leukotriene B4 via a GM-CSF/PU.1 axis.
Serezani CH, Kane S, Collins L, Morato-Marques M, Osterholzer JJ, Peters-Golden M
(2012) J Immunol 189: 906-15
MeSH Terms: Animals, Candida albicans, Cells, Cultured, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Lectins, C-Type, Leukotriene B4, Macrophages, Alveolar, Macrophages, Peritoneal, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins, Receptors, Leukotriene B4, Trans-Activators, Transcription, Genetic
Show Abstract · Added May 4, 2017
Pattern recognition receptors for fungi include dectin-1 and mannose receptor, and these mediate phagocytosis, as well as production of cytokines, reactive oxygen species, and the lipid mediator leukotriene B(4) (LTB(4)). The influence of G protein-coupled receptor ligands such as LTB(4) on fungal pattern recognition receptor expression is unknown. In this study, we investigated the role of LTB(4) signaling in dectin-1 expression and responsiveness in macrophages. Genetic and pharmacologic approaches showed that LTB(4) production and signaling through its high-affinity G protein-coupled receptor leukotriene B(4) receptor 1 (BLT1) direct dectin-1-dependent binding, ingestion, and cytokine production both in vitro and in vivo. Impaired responses to fungal glucans correlated with lower dectin-1 expression in macrophages from leukotriene (LT)- and BLT1-deficent mice than their wild-type counterparts. LTB(4) increased the expression of the transcription factor responsible for dectin-1 expression, PU.1, and PU.1 small interfering RNA abolished LTB(4)-enhanced dectin-1 expression. GM-CSF controls PU.1 expression, and this cytokine was decreased in LT-deficient macrophages. Addition of GM-CSF to LT-deficient cells restored expression of dectin-1 and PU.1, as well as dectin-1 responsiveness. In addition, LTB(4) effects on dectin-1, PU.1, and cytokine production were blunted in GM-CSF(-/-) macrophages. Our results identify LTB(4)-BLT1 signaling as an unrecognized controller of dectin-1 transcription via GM-CSF and PU.1 that is required for fungi-protective host responses.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates.
Kotecha N, Flores NJ, Irish JM, Simonds EF, Sakai DS, Archambeault S, Diaz-Flores E, Coram M, Shannon KM, Nolan GP, Loh ML
(2008) Cancer Cell 14: 335-43
MeSH Terms: Adult, Biomarkers, Tumor, Cell Proliferation, Cells, Cultured, Child, Disease Progression, Flow Cytometry, Gene Expression Regulation, Neoplastic, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Janus Kinase 2, Leukemia, Myelomonocytic, Juvenile, Myeloproliferative Disorders, Neoplasm Staging, Phosphorylation, Recurrence, STAT5 Transcription Factor, Signal Transduction, Treatment Outcome
Show Abstract · Added February 15, 2013
Progress in understanding the molecular pathogenesis of human myeloproliferative disorders (MPDs) has led to guidelines incorporating genetic assays with histopathology during diagnosis. Advances in flow cytometry have made it possible to simultaneously measure cell type and signaling abnormalities arising as a consequence of genetic pathologies. Using flow cytometry, we observed a specific evoked STAT5 signaling signature in a subset of samples from patients suspected of having juvenile myelomonocytic leukemia (JMML), an aggressive MPD with a challenging clinical presentation during active disease. This signature was a specific feature involving JAK-STAT signaling, suggesting a critical role of this pathway in the biological mechanism of this disorder and indicating potential targets for future therapies.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients.
Lavin VA, Hamid R, Patterson J, Alford C, Ho R, Yang E
(2008) Pediatr Blood Cancer 51: 298-302
MeSH Terms: Female, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Infant, Leukemia, Myelomonocytic, Juvenile, Mutation, Noonan Syndrome, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Receptors, Androgen
Show Abstract · Added March 5, 2014
Noonan syndrome (NS) patients are at increased risk for developing juvenile myelomonocytic leukemia (JMML), an aggressive clonal disorder of aberrant cell proliferation. Many NS patients exhibit spontaneously remitting monocytosis and transient myeloproliferation. The distinction between bone marrow hyperproliferation due to germline mutation and leukemia resulting from clonal transformation can be difficult in NS patients. The GM-CSF hypersensitivity assay, diagnostic of sporadic JMML, can be positive in NS patients at baseline. In this report, we demonstrate the utility of determining the clonal status of the monocyte population by the HUMARA assay in distinguishing JMML and benign myeloproliferation in female NS patients.
1 Communities
2 Members
0 Resources
9 MeSH Terms
K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells.
Van Meter ME, Díaz-Flores E, Archard JA, Passegué E, Irish JM, Kotecha N, Nolan GP, Shannon K, Braun BS
(2007) Blood 109: 3945-52
MeSH Terms: Animals, Cell Proliferation, Extracellular Signal-Regulated MAP Kinases, Granulocyte-Macrophage Colony-Stimulating Factor, Hematopoietic Stem Cells, Mice, Mice, Transgenic, Myeloproliferative Disorders, Neoplastic Stem Cells, Point Mutation, Proto-Oncogene Proteins p21(ras), Ribosomal Protein S6 Kinases, STAT5 Transcription Factor, Signal Transduction
Show Abstract · Added February 15, 2013
Defining how cancer-associated mutations perturb signaling networks in stem/progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic Kras(G12D) allele on phosphorylated signaling molecules in primary c-kit(+) lin(-/low) hematopoietic stem/progenitor cells. Comparison of wild-type and Kras(G12D) c-kit(+) lin(-/low) cells shows that K-Ras(G12D) expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas Kras(G12D) cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell-targeted interventions.
1 Communities
1 Members
0 Resources
14 MeSH Terms
Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny.
Bezbradica JS, Gordy LE, Stanic AK, Dragovic S, Hill T, Hawiger J, Unutmaz D, Van Kaer L, Joyce S
(2006) Immunity 25: 487-97
MeSH Terms: Animals, Cell Differentiation, Cells, Cultured, Cytokines, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Killer Cells, Natural, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Receptor, Macrophage Colony-Stimulating Factor, T-Lymphocyte Subsets, Thymus Gland
Show Abstract · Added December 10, 2013
Invariant natural killer T (iNKT) cell-derived cytokines have important functions in inflammation, host defense, and immunoregulation. Yet, when and how iNKT cells undergo effector differentiation, which endows them with the capacity to rapidly secrete cytokines upon activation, remains unknown. We discovered that granulocyte-macrophage colony-stimulating factor (Csf-2)-deficient mice developed iNKT cells that failed to respond to the model antigen alpha-galactosylceramide because of an intrinsic defect in the fusion of secretory vesicles with the plasma membrane. Exogenous Csf-2 corrected the functional defect only when supplied during the development of thymic, but not mature, splenic Csf-2-deficient iNKT cells. Thus, we ascribe a unique function to Csf-2, which regulates iNKT cell effector differentiation during development by a mechanism that renders them competent for cytokine secretion.
0 Communities
3 Members
0 Resources
15 MeSH Terms
Role of granulocyte macrophage colony-stimulating factor during gram-negative lung infection with Pseudomonas aeruginosa.
Ballinger MN, Paine R, Serezani CH, Aronoff DM, Choi ES, Standiford TJ, Toews GB, Moore BB
(2006) Am J Respir Cell Mol Biol 34: 766-74
MeSH Terms: Animals, Chemokines, CXC, Colony Count, Microbial, Cytokines, Eicosanoids, Granulocyte-Macrophage Colony-Stimulating Factor, Leukocytes, Lung, Macrophages, Alveolar, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis, Pneumonia, Bacterial, Pseudomonas Infections, Pseudomonas aeruginosa
Show Abstract · Added May 4, 2017
Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates survival, proliferation, differentiation, and function of myeloid cells. Recently, GM-CSF has been shown to be important for normal pulmonary homeostasis. We report that GM-CSF is induced in lung leukocytes during infection with Gram-negative bacteria. Therefore, we postulated that deficiencies in GM-CSF would increase susceptibility to Gram-negative infection in vivo. After an intratracheal inoculum with Pseudomonas aeruginosa, GM-CSF-/- mice show decreased survival compared with wild-type mice. GM-CSF-/- mice show increased lung, spleen, and blood bacterial CFU. GM-CSF-/- mice are defective in the production of cysteinyl leukotrienes, prostaglandin E2, macrophage inflammatory protein, and keratinocyte-derived chemokine in lung leukocytes postinfection. Despite these defects, inflammatory cell recruitment is not diminished at 6 or 24 h postinfection, and the functional activity of polymorphonuclear leukocytes from the lung and peritoneum against P. aeruginosa is enhanced in GM-CSF-/- mice. In contrast, alveolar macrophage (AM) phagocytosis, killing, and H2O2 production are defective in GM-CSF-/- mice. Although the absence of GM-CSF has profound effects on AMs, peritoneal macrophages seem to have normal bactericidal activities in GM-CSF-/- mice. Defects in AM function may be related to diminished levels of IFN-gamma and TNF-alpha postinfection. Thus, GM-CSF-/- mice are more susceptible to lung infection with P. aeruginosa as a result of impaired AM function.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Inhibition of antitumor immunity by invariant natural killer T cells in a T-cell lymphoma model in vivo.
Renukaradhya GJ, Sriram V, Du W, Gervay-Hague J, Van Kaer L, Brutkiewicz RR
(2006) Int J Cancer 118: 3045-53
MeSH Terms: Animals, Antigens, CD1, Antigens, CD1d, Cell Line, Tumor, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor, Interferon-gamma, Interleukin-13, Killer Cells, Natural, Lymphocyte Activation, Lymphoma, T-Cell, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Time Factors
Show Abstract · Added December 10, 2013
We have investigated the role of the host's CD1d-dependent innate antitumor immune response in a murine T-cell lymphoma model in vivo. We found that C57BL/6 wildtype (WT) mice inoculated with RMA/S cells transfected with murine CD1d1 died at the same rate as mice inoculated with vector-transfected cells. In contrast, natural killer T (NKT) cell-deficient CD1d or Jalpha18 knockout mice inoculated with CD1d-transfected RMA/S cells survived significantly longer than mice inoculated with vector-transfected RMA/S cells, implicating the involvement of invariant NKT (iNKT) cells in inhibiting antitumor activity in vivo. In contrast to the mutant mice, which produced more of the proinflammatory cytokines IFN-gamma and GM-CSF, WT mice produced significantly elevated amounts of IL-13. Antitumor activity in the knockout mice was not due to the development of CD1d-specific cytotoxic T lymphocytes or circulating antibodies. However, iNKT cell numbers were elevated in tumor-bearing mice. Thus, iNKT cells may be playing a negative role in the host's antitumor immune response against T-cell lymphomas in a CD1d-dependent manner.
Copyright 2006 Wiley-Liss, Inc.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli.
Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN
(2005) J Neurochem 95: 437-45
MeSH Terms: Animals, Arachidonic Acid, Bone Marrow Cells, Cells, Cultured, Cytokines, DNA, Complementary, Encephalomyelitis, Autoimmune, Experimental, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor, Inflammation, Interferon-gamma, Macrophage Activation, Macrophages, Mass Spectrometry, Mice, Mice, Inbred C57BL, Microglia, RNA, Messenger, Receptor, Cannabinoid, CB2, Recombinant Fusion Proteins, Reverse Transcriptase Polymerase Chain Reaction, Spinal Cord, Up-Regulation
Show Abstract · Added March 26, 2019
The cannabinoid system is known to be important in neuronal regulation, but is also capable of modulating immune function. Although the CNS resident microglial cells have been shown to express the CB2 subtype of cannabinoid receptor during non-immune-mediated pathological conditions, little is known about the expression of the cannabinoid system during immune-mediated CNS pathology. To examine this question, we measured CB2 receptor mRNA expression in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) and, by real-time PCR, found a 100-fold increase in CB2 receptor mRNA expression during EAE onset. We next determined whether microglial cells specifically express the CB2 receptor during EAE, and found that activated microglial cells expressed 10-fold more CB2 receptor than microglia in the resting state. To determine the signals required for the up-regulation of the CB2 receptor, we cultured microglial cells with combinations of gamma-interferon (IFN-gamma) and granulocyte) macrophage-colony stimulating factor (GM-CSF), which both promote microglial cell activation and are expressed in the CNS during EAE, and found that they synergized, resulting in an eight to 10-fold increase in the CB2 receptor. We found no difference in the amount of the CB2 receptor ligand, 2-arachidonylglycerol (2-AG), in the spinal cord during EAE. These data demonstrate that microglial cell activation is accompanied by CB2 receptor up-regulation, suggesting that this receptor plays an important role in microglial cell function in the CNS during autoimmune-induced inflammation.
0 Communities
1 Members
0 Resources
MeSH Terms