Activated Dendritic Cells From Bone Marrow Cells of Mice Receiving Cytokine-Expressing Tumor Cells Are Associated With the Enhanced Survival of Mice Bearing Syngeneic Tumors

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4328-4335
Author(s):  
Shin-ichiro Fujii ◽  
Hirofumi Hamada ◽  
Koji Fujimoto ◽  
Taizo Shimomura ◽  
Makoto Kawakita
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Interleukin 4 ◽  
Gm Csf ◽  
Tumor Bearing ◽  
Macrophage Colony

Dendritic cells (DCs), which phagocytose antigens and subsequently proliferate and migrate, may be the most powerful antigen-presenting cells that activate naive T cells. To determine their role in the immune response to tumors, we used WEHI-3B murine leukemia cells transduced with adenovirus vectors expressing cytokines. We found that mixtures of irradiated cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) plus those expressing interleukin-4 (IL-4) or tumor necrosis factor  (TNF) protected mice against WEHI-3B–induced leukemias. When bone marrow mononuclear cells (BMMNCs) obtained from mice that had been injected with irradiated, cytokine-expressing tumor cells were injected into tumor-bearing mice, the survival of the latter was significantly prolonged; the longest survival was observed in mice receiving BMMNCs containing an increased number of DCs from animals injected with a mixture of tumor cells expressing GM-CSF with those expressing IL-4. Assay for antileukemic effects in spleen of the latter animals showed specific antitumor cytotoxicity against WEHI-3B, suggesting that DCs from donor mice activate specific T cells in the tumor-bearing recipients. These results suggest that the infusion of syngeneic BMMNCs stimulated with cytokine-expressing tumor cells may be effective in treating certain types of tumors.

Activated Dendritic Cells From Bone Marrow Cells of Mice Receiving Cytokine-Expressing Tumor Cells Are Associated With the Enhanced Survival of Mice Bearing Syngeneic Tumors

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4328-4335 ◽  
Author(s):  
Shin-ichiro Fujii ◽  
Hirofumi Hamada ◽  
Koji Fujimoto ◽  
Taizo Shimomura ◽  
Makoto Kawakita
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Interleukin 4 ◽  
Gm Csf ◽  
Tumor Bearing ◽  
Macrophage Colony

Abstract Dendritic cells (DCs), which phagocytose antigens and subsequently proliferate and migrate, may be the most powerful antigen-presenting cells that activate naive T cells. To determine their role in the immune response to tumors, we used WEHI-3B murine leukemia cells transduced with adenovirus vectors expressing cytokines. We found that mixtures of irradiated cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) plus those expressing interleukin-4 (IL-4) or tumor necrosis factor  (TNF) protected mice against WEHI-3B–induced leukemias. When bone marrow mononuclear cells (BMMNCs) obtained from mice that had been injected with irradiated, cytokine-expressing tumor cells were injected into tumor-bearing mice, the survival of the latter was significantly prolonged; the longest survival was observed in mice receiving BMMNCs containing an increased number of DCs from animals injected with a mixture of tumor cells expressing GM-CSF with those expressing IL-4. Assay for antileukemic effects in spleen of the latter animals showed specific antitumor cytotoxicity against WEHI-3B, suggesting that DCs from donor mice activate specific T cells in the tumor-bearing recipients. These results suggest that the infusion of syngeneic BMMNCs stimulated with cytokine-expressing tumor cells may be effective in treating certain types of tumors.

Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression

2001 ◽  
Vol 7 (2) ◽  
pp. 95-99 ◽  
Author(s):  
Yu-Min Huang ◽  
Mathilde Kouwenhoven ◽  
Ya-Ping Jin ◽  
Rayomand Press ◽  
Wen-Xin Huang ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Interleukin 4 ◽  
Gm Csf ◽  
The Central Nervous System ◽  
Macrophage Colony ◽  
Antigen Presenting

Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-b. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.

scholarly journals Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha.

1995 ◽  
Vol 182 (4) ◽  
pp. 1111-1119 ◽  
Author(s):  
J W Young ◽  
P Szabolcs ◽  
M A Moore
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Bone Marrow Cells ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Kit Ligand ◽  
Human Cd34 ◽  
Macrophage Colony

Several cytokines, especially granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha), have been identified that foster the development of dendritic cells from blood and bone marrow precursors in suspension cultures. These precursors are reported to be infrequent or to yield small numbers of dendritic cells in colony-forming assays. Here we readily identify dendritic cell colony-forming units (CFU-DC) that give rise to pure dendritic cell colonies. Human CD34+ bone marrow progenitors were expanded in semi-solid cultures with serum-replete medium containing c-kit-ligand, GM-CSF, and TNF-alpha. The addition of TNF-alpha to GM-CSF did not alter the number of typical GM colonies but did generate pure dendritic cell colonies that accounted for approximately 40% of the total colony growth. When the two distinct types of colonies were plucked from methylcellulose and tested for T cell-stimulatory activity in the mixed leukocyte reaction, the potency of colony-derived dendritic cells exceeded that of CFU-GM progeny from the same cultures by at least 1.5-2 logs. Immunophenotyping and cytochemical staining of the CFU-DC-derived progeny was also characteristic of dendritic cells. Other myeloid cells were not identified in these colonies. The addition of c-kit-ligand to GM-CSF- and TNF-alpha-supplemented suspensions of CD34+ bone marrow cells expanded CFU-DCs almost 100-fold by 14 d. We conclude that normal human CD34+ bone marrow cells include substantial numbers of clonogenic progenitors, distinct from CFU-GMs, that can give rise to pure dendritic cell colonies. These CFU-DCs can be expanded for several weeks by in vitro culture with c-kit-ligand, and their differentiation requires exogenous TNF-alpha in addition to GM-CSF. We speculate that this dendritic cell-committed pathway may in the steady state contribute cells to the epidermis and afferent lymph, where dendritic cells are the principal myeloid cell type, and may increase the numbers of these specialized antigen-presenting cells during T cell-mediated immune responses.

Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing tumor vaccines

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3011-3019
Author(s):  
Ivan Borrello ◽  
Eduardo M. Sotomayor ◽  
Frédérique-Marie Rattis ◽  
Sara K. Cooke ◽  
Lingping Gu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Tumor Cells ◽  
Immune Reconstitution ◽  
Autologous Tumor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

For many cancers, autologous bone marrow transplantation (BMT) achieves a minimal residual disease state, yet relapse rates remain high. Using a syngeneic murine bone marrow transplant model, we demonstrate that vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing autologous tumor cells is effective in the post-BMT period and actually results in a greater tumor-free survival than vaccination in the nontransplant setting. Employing T cells specific for a model tumor-antigen, we find that transplantation of the tumor-bearing host results in a massive expansion and activation of tumor-specific T cells in the early posttransplant period, but this response rapidly declines in association with tumor progression. Immunization with irradiated GM-CSF tumor cells during the period of immune reconstitution results in the sustained amplification and activation of this response that closely correlates with freedom from relapse. These results demonstrate the feasibility of integrating GM-CSF vaccines in the postautologous BMT setting and suggest mechanisms that may contribute to the observed efficacy of immunization during the critical period of immune reconstitution.

A combined local treatment with anti-PD-1 antibody and bone marrow derived dendritic cells after x-ray irradiation to subcutaneous melanoma in a murine model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14541-e14541
Author(s):  
Yuzi Wang ◽  
Lue Sun ◽  
Xiaokang Li ◽  
Koji Tsuboi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Combination Treatment ◽  
Bone Marrow Cells ◽  
Local Treatment ◽  
Activated T Cells ◽  
X Ray

e14541 Background: In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are supposed to be incorporated into dendritic cells (DCs), and sequentially rendering T-cells activated and proliferated. However, it has been clarified that activated T-cells are killed by PD-L1 ligands on tumor cells which bind to PD-1 receptors on T-cells, consequently suppressing systemic cellular immunological response. To improve local control and prevent metastases after localized radiotherapy, we examined whether the combination of anti-PD-1 antibody and bone marrow derived DCs (BM-DCs) can enhance both the local and systemic antitumor immunoreactions after localized X-ray irradiation in a murine melanoma model. Methods: BM-DCs were induced by using GM-CSF and IL-4 from bone marrow cells taken from the femur and tibia of C57BL/6 mice. Syngeneic B16 melanoma cells implanted subcutaneously at the left thighs of C57BL/6 mice were irradiated with X-ray (8 Gy) 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced DCs were injected directly to the tumor site, similarly, after 1, 3, 5 days from irradiation, anti-PD-1 antibody were injected intraperitoneally. To examine the systemic immunoreaction, B16 cells were also inoculated to the right side 4 days after the left side inoculation, and treated with the same protocols only on the left side. The size of tumors was monitored and survival analyses were performed. Results: The induced DCs showed the ability to incorporate antigens and to prime and proliferate T-cells in vitro. The combination treatment of anti-PD-1 antibody, BM-DCs and X-ray irradiation showed a significant delay of tumor growth compared to single or double combination treatments in vivo. In addition, this triple combination treatment significantly inhibited the tumor growth on the other side compared to other treatments. Conclusions: DCs and anti-PD-1 antibody significantly enhanced the antitumor effect of X-ray irradiation and prolonged the survival time. This combination also can induce a strong systemic antitumor immunoreaction which could treat metastatic tumors.

Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing tumor vaccines

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3011-3019 ◽  
Author(s):  
Ivan Borrello ◽  
Eduardo M. Sotomayor ◽  
Frédérique-Marie Rattis ◽  
Sara K. Cooke ◽  
Lingping Gu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Tumor Cells ◽  
Immune Reconstitution ◽  
Autologous Tumor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract For many cancers, autologous bone marrow transplantation (BMT) achieves a minimal residual disease state, yet relapse rates remain high. Using a syngeneic murine bone marrow transplant model, we demonstrate that vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing autologous tumor cells is effective in the post-BMT period and actually results in a greater tumor-free survival than vaccination in the nontransplant setting. Employing T cells specific for a model tumor-antigen, we find that transplantation of the tumor-bearing host results in a massive expansion and activation of tumor-specific T cells in the early posttransplant period, but this response rapidly declines in association with tumor progression. Immunization with irradiated GM-CSF tumor cells during the period of immune reconstitution results in the sustained amplification and activation of this response that closely correlates with freedom from relapse. These results demonstrate the feasibility of integrating GM-CSF vaccines in the postautologous BMT setting and suggest mechanisms that may contribute to the observed efficacy of immunization during the critical period of immune reconstitution.

scholarly journals Feline immunodeficiency virus infection is enhanced by feline bone marrow-derived dendritic cells

2007 ◽  
Vol 88 (1) ◽  
pp. 251-258 ◽  
Author(s):  
F. J. U. M. van der Meer ◽  
N. M. P. Schuurman ◽  
H. F. Egberink
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Feline Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Interleukin 4 ◽  
Peripheral Blood Mononuclear ◽  
Feline Immunodeficiency Virus Infection ◽  
Immunodeficiency Virus ◽  
Macrophage Colony

In the pathogenesis of feline immunodeficiency virus (FIV) infection, feline dendritic cells (feDCs) are thought to play an important role. As with DCs in other species, feDCs are believed to transport virus particles to lymph nodes and transfer them to lymphocytes. Our investigation has focused on the ability of feDCs to influence the infection of syngeneic peripheral blood mononuclear cells (PBMCs) and allogeneic thymocytes. feDCs were derived from bone marrow mononuclear cells that were cultured under the influence of feline interleukin-4 and feline granulocyte–macrophage colony-stimulating factor. By using these feDCs in co-culture with resting PBMCs, an upregulation of FIV replication was shown. An enhancement of FIV infection was also detected when co-cultures of feDCs/feline thymocytes were infected. To obtain this enhancement, direct contact of the cells in the co-culture was necessary; transwell cultures showed that the involvement of only soluble factors produced by feDCs in this process is not likely. These feDCs were also able to induce the proliferation of resting thymocytes, which might explain the enhanced FIV replication observed. Together, these data suggest that feDCs have abilities similar to those shown for simian and human DCs in the interaction with leukocytes. This system is suitable for further investigations of the interplay of DC and T cells during FIV infection in vitro.

scholarly journals Heme-stress activated NRF2 skews fate trajectories of bone marrow cells from dendritic cells towards red pulp-like macrophages in hemolytic anemia

2022 ◽  
Author(s):  
Florence Vallelian ◽  
Raphael M. Buzzi ◽  
Marc Pfefferlé ◽  
Ayla Yalamanoglu ◽  
Irina L. Dubach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Sickle Cell Disease ◽  
Bone Marrow Cells ◽  
Cell Disease ◽  
Secondary Immunodeficiency ◽  
Gm Csf ◽  
Bone Marrow Cultures ◽  
Marrow Cultures

AbstractHeme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias, such as sickle cell disease. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Since chronic heme-stress is noxious for macrophages, erythrophagocytes in the spleen are continuously replenished from bone marrow-derived progenitors. Here, we hypothesized that adaptation to heme stress progressively shifts differentiation trajectories of bone marrow progenitors to expand the capacity of heme-handling monocyte-derived macrophages at the expense of the homeostatic generation of dendritic cells, which emerge from shared myeloid precursors. This heme-induced redirection of differentiation trajectories may contribute to hemolysis-induced secondary immunodeficiency. We performed single-cell RNA-sequencing with directional RNA velocity analysis of GM-CSF-supplemented mouse bone marrow cultures to assess myeloid differentiation under heme stress. We found that heme-activated NRF2 signaling shifted the differentiation of bone marrow cells towards antioxidant, iron-recycling macrophages, suppressing the generation of dendritic cells in heme-exposed bone marrow cultures. Heme eliminated the capacity of GM-CSF-supplemented bone marrow cultures to activate antigen-specific CD4 T cells. The generation of functionally competent dendritic cells was restored by NRF2 loss. The heme-induced phenotype of macrophage expansion with concurrent dendritic cell depletion was reproduced in hemolytic mice with sickle cell disease and spherocytosis and associated with reduced dendritic cell functions in the spleen. Our data provide a novel mechanistic underpinning of hemolytic stress as a driver of hyposplenism-related secondary immunodeficiency.

scholarly journals Differentiation of human dendritic cells from monocytes in vitro using granulocyte-macrophage colony stimulating factor and low concentration of interleukin-4

2003 ◽  
Vol 60 (5) ◽  
pp. 531-538 ◽  
Author(s):  
Miodrag Colic ◽  
Dusan Jandric ◽  
Zorica Stojic-Vukanic ◽  
Jelena Antic-Stankovic ◽  
Petar Popovic ◽  
...  
Keyword(s):  
T Cells ◽  
Interleukin 4 ◽  
Adherent Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Alloreactive T Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Dendritic Cells ◽  
Stimulating Factor

Several laboratories have developed culture systems that allow the generation of large numbers of human dendritic cells (DC) from monocytes using granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-4 (IL-4). In this work we provided evidence that GM-CSF (100 ng/ml) in combination with a low concentration of IL-4 (5 ng/ml) was efficient in the generation of immature, non-adherent, monocyte-derived DC as the same concentration of GM-CSF, and ten times higher concentration of IL-4 (50 ng/ml). This conclusion was based on the similar phenotype profile of DC such as the expression of CD1a, CD80, CD86, and HLA-DR, down-regulation of CD14, and the absence of CD83, as well as on their similar allostimulatory activity for T cells. A higher number of cells remained adherent in cultures with lower concentrations of IL-4 than in cultures with higher concentrations of the cytokine. However, most of these adherent cells down-regulated CD14 and stimulated the proliferation of alloreactive T cells. In contrast adherent cells cultivated with GM-CSF alone were predominantly macrophages as judged by the expression of CD14 and the inefficiency to stimulate alloreactive T cells. DC generated in the presence of lower concentrations of IL-4 had higher proapoptotic potential for the Jurkat cell line than DC differentiated with higher concentrations of IL-4, suggesting their stronger cytotoxic, anti-tumor effect.

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