Effects of gamma-Irradiation on Acute Myelogenous Leukemia Blasts: In Vitro Studies of Proliferation, Constitutive Cytokine Secretion, and Accessory Cell Function During T Cell Activation

1999 ◽  
Vol 8 (4) ◽  
pp. 431-441 ◽  
Author(s):  
Oystein Bruserud ◽  
Elling Ulvestad
Keyword(s):  
T Cell ◽  
Gamma Irradiation ◽  
T Cell Activation ◽  
Acute Myelogenous Leukemia ◽  
Cell Activation ◽  
Cell Function ◽  
Myelogenous Leukemia ◽  
Accessory Cell ◽  
Acute Myelogenous

scholarly journals TRPM2 Is Not Required for T-Cell Activation and Differentiation

2022 ◽  
Vol 12 ◽  
Author(s):  
Niels C. Lory ◽  
Mikolaj Nawrocki ◽  
Martina Corazza ◽  
Joanna Schmid ◽  
Valéa Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Activation Markers

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

Abstract We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

scholarly journals GABAA receptor α4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model

2017 ◽  
Vol 313 (2) ◽  
pp. L406-L415 ◽  
Author(s):  
Gene T. Yocum ◽  
Damian L. Turner ◽  
Jennifer Danielsson ◽  
Matthew B. Barajas ◽  
Yi Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Asthma Model

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABAARs, particularly isoforms containing α4-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAAR α4-subunit global knockout (KO; Gabra40/0) mice. Wild-type (WT) and Gabra4 KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and Gabra4 KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( P = not significant; n = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in Gabra4 KO mice ( P < 0.05, n = 8). Moreover, the Gabra4 KO mice demonstrated increased eosinophilic lung infiltration ( P < 0.05; n = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; P < 0.01, n = 4). In vitro, Gabra4 KO CD4+ cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4+ cells. These data suggest that the GABAAR α4-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAAR α4-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

scholarly journals Platelet-derived growth factor is a potent biologic response modifier of T cells.

1991 ◽  
Vol 174 (6) ◽  
pp. 1323-1333 ◽  
Author(s):  
R A Daynes ◽  
T Dowell ◽  
B A Araneo
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Platelet Derived Growth Factor ◽  
Free Medium ◽  
Ifn Gamma ◽  
Serum Free

Freshly isolated lymph node (LN) cells cultured in serum-containing medium were restricted to produce primarily interleukin 2 (IL-2) subsequent to T cell activation. Only minimal amounts of IL-4, IL-5, or interferon gamma (IFN-gamma) were produced under these conditions. Similar populations of LN cells cultured in serum-free medium were able to produce a variety of lymphokines after T cell activation, with the relative quantities of each species being dependent upon the lymphoid organ source of the lymphocytes. A similar relationship in the patterns of lymphokines produced by activated T cell hybridomas maintained under serum-free conditions was also observed, whereas activation in serum-supplemented media resulted in a predominant restriction to the secretion of IL-2. Additional studies determined that the entity in serum responsible for restricting T cell function in vitro was platelet-derived growth factor (PDGF). The PDGF-BB isoform was established to be the most active in the regulation of T cell function, enhancing IL-2 while depressing the production of IL-4, IL-5, and IFN-gamma at concentrations below 1 ng/ml. PDGF-AB was also found to be quite active, however, this isoform of PDGF was incapable of influencing IFN-gamma production at the concentrations tested. PDGF-AA was very weakly active. It therefore appears that PDGF, acting primarily through a beta receptor subunit (either alpha/beta- or beta/beta-type receptors) is able to influence profoundly the behavior of T cells, with some of its modulatory effects exhibiting isoform specificity. This is reflected by an enhancement in the production of IL-2, while simultaneously depressing the secretion of IL-4, IL-5, and IFN-gamma (PDGF-BB only) after T cell activation. Kinetic studies, where cell supernatants were analyzed both 24 and 48 h after T cell activation, suggested that "desensitization" to PDGF influences can occur naturally in vitro. Those species of lymphokines that were inhibited by PDGF over the first 24 h after activation could be produced at normal levels over the subsequent 24-h period. Finally, lymphokines maintained in the presence of PDGF-BB for greater than 24 h before their activation lost sensitivity to this growth factor. These cells regained responsiveness to PDGF after an additional incubation period in PDGF-free medium. Collectively, our data imply that the pattern of T cell lymphokines produced, plus the kinetics of their production after activation, are being controlled by the potent serum growth factor PDGF.(ABSTRACT TRUNCATED AT 400 WORDS)

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