scholarly journals High serum colony-stimulating activity of leukocytopenic patients after intravenous infusions of human urinary colony-stimulating factor

Blood ◽  
1983 ◽  
Vol 62 (3) ◽  
pp. 685-688
Author(s):  
K Motoyoshi ◽  
F Takaku ◽  
Y Miura
Keyword(s):  
Low Dose ◽  
High Serum ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Intravenous Infusions ◽  
Colony Stimulating Activity ◽  
Stimulating Factor ◽  
Stimulation Of

Eight adult patients suffering from leukocytopenia have been injected by droplet intravenous infusions with partially purified human urinary colony-stimulating factor (CSFHU), which stimulated human monocytes to produce colony-stimulating activity (CSA) in vitro. Three of eight patients were injected with low-dose CSFHU and five with high-dose CSFHU. The infusion of high-dose CSFHU led to a slightly earlier rise in absolute neutrophil counts and a higher CSA level in the serum, as compared to noninjected leukocytopenic patients. There was little toxicity associated with it. Human urinary colony-stimulating factor used in the clinical studies did not have any CSA in vitro in the presence or absence of the patients' sera. These data may suggest that the intravenous infusion of CSFHU increased the serum CSA level, probably through the stimulation of CSA-producing cells in vivo.

scholarly journals High serum colony-stimulating activity of leukocytopenic patients after intravenous infusions of human urinary colony-stimulating factor

Blood ◽  
1983 ◽  
Vol 62 (3) ◽  
pp. 685-688 ◽  
Author(s):  
K Motoyoshi ◽  
F Takaku ◽  
Y Miura
Keyword(s):  
Low Dose ◽  
High Serum ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Intravenous Infusions ◽  
Colony Stimulating Activity ◽  
Stimulating Factor ◽  
Stimulation Of

Abstract Eight adult patients suffering from leukocytopenia have been injected by droplet intravenous infusions with partially purified human urinary colony-stimulating factor (CSFHU), which stimulated human monocytes to produce colony-stimulating activity (CSA) in vitro. Three of eight patients were injected with low-dose CSFHU and five with high-dose CSFHU. The infusion of high-dose CSFHU led to a slightly earlier rise in absolute neutrophil counts and a higher CSA level in the serum, as compared to noninjected leukocytopenic patients. There was little toxicity associated with it. Human urinary colony-stimulating factor used in the clinical studies did not have any CSA in vitro in the presence or absence of the patients' sera. These data may suggest that the intravenous infusion of CSFHU increased the serum CSA level, probably through the stimulation of CSA-producing cells in vivo.

scholarly journals In vivo stimulation of megakaryocytopoiesis by recombinant murine granulocyte-macrophage colony-stimulating factor

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1473-1480
Author(s):  
AM Vannucchi ◽  
A Grossi ◽  
D Rafanelli ◽  
PR Ferrini
Keyword(s):  
Bone Marrow ◽  
Blood Platelets ◽  
Colony Stimulating Factor ◽  
Platelet Production ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

Murine recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) was injected in mice, and the effects on bone marrow, splenic megakaryocytes, megakaryocyte precursors (megakaryocyte colony-forming units [CFU-Meg]) were evaluated. In mice injected three times a day for 6 days with 12,000 to 120,000 U rGM-CSF, no significant modification of both platelet levels and mean platelet volume was observed, while there was a twofold increase in blood neutrophils. However, the rate of platelet production, as assessed by the measurement of 75selenomethionine incorporation into blood platelets, was On the contrary, administration of up to 384,000 U rGM-CSF two times a day for 2 days, as for a typical “thrombopoietin assay,” failed to modify platelet production. A significant dose-related increase in the number of splenic megakaryocytes occurred in mice receiving 60,000 to 120,000 U rGM-CSF, while a slight increase in the number of bone marrow megakaryocytes was observed in mice injected with 120,000 U rGM-CSF. The proportion of bone marrow megakaryocytes with a size less than 18 microns and greater than 35 microns resulted significantly higher in mice receiving rGM-CSF in comparison with controls; an increase in the percentage of splenic megakaryocytes greater than 35 microns was also observed. A statistically significant increase in the total spleen content of CFU-Meg was observed after administration of 90,000 and 120,000 U rGM-CSF three times a day for 6 days, while no effect on bone marrow CFU-Meg was recorded, irrespective of the dose delivered. Finally, 24 hours after a single intravenous injection of rGM-CSF, there was a significant increase in the proportion of CFU-Meg in S- phase, with the splenic progenitors being more sensitive than bone marrow-derived CFU-Meg. These data indicate that rGM-CSF has in vivo megakaryocyte stimulatory activity, and are consistent with previous in vitro observations. However, an effective stimulation of megakaryocytopoiesis in vivo, bringing about an increase in the levels of blood platelets, may require interaction of rGM-CSF with other cytokines.

scholarly journals Humoral Stimulators of Granulocyte Production

Blood ◽  
1973 ◽  
Vol 41 (1) ◽  
pp. 73-78 ◽  
Author(s):  
G. Rothstein ◽  
E. H. Hügl ◽  
P. A. Chervenick ◽  
J. W. Athens ◽  
J. Macfarlane
Keyword(s):  
High Serum ◽  
Colony Stimulating Factor ◽  
Short Term ◽  
Single Substance ◽  
Data Support ◽  
Csf Levels ◽  
Stimulating Factor

Abstract These studies were designed to determine whether colony stimulating factor (CSF) and diffusible granulocytopoietic stimulator (DGS) represented a single substance which stimulates the production of granulocytes in vitro and in vivo. The effect of endogenous CSF upon DGS activity was studied after injection of 40 µg endotoxin. This resuited in both DGS activity and high serum CSF levels, but the time of appearance and duration of the two activities followed different patterns. In particular, CSF peaked and was declining 24 hr following endotoxin at which time DGS was not yet detectable. Then, as serum CSF fell, the DGS activity rose. These data support the concept that the DGS activity detectable with short term Millipore chamber cultures is not due to CSF and suggests the effects of CSF in vitro and DGS in vivo are due to different factors.

scholarly journals In vivo stimulation of megakaryocytopoiesis by recombinant murine granulocyte-macrophage colony-stimulating factor

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1473-1480 ◽  
Author(s):  
AM Vannucchi ◽  
A Grossi ◽  
D Rafanelli ◽  
PR Ferrini
Keyword(s):  
Bone Marrow ◽  
Blood Platelets ◽  
Colony Stimulating Factor ◽  
Platelet Production ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

Abstract Murine recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) was injected in mice, and the effects on bone marrow, splenic megakaryocytes, megakaryocyte precursors (megakaryocyte colony-forming units [CFU-Meg]) were evaluated. In mice injected three times a day for 6 days with 12,000 to 120,000 U rGM-CSF, no significant modification of both platelet levels and mean platelet volume was observed, while there was a twofold increase in blood neutrophils. However, the rate of platelet production, as assessed by the measurement of 75selenomethionine incorporation into blood platelets, was On the contrary, administration of up to 384,000 U rGM-CSF two times a day for 2 days, as for a typical “thrombopoietin assay,” failed to modify platelet production. A significant dose-related increase in the number of splenic megakaryocytes occurred in mice receiving 60,000 to 120,000 U rGM-CSF, while a slight increase in the number of bone marrow megakaryocytes was observed in mice injected with 120,000 U rGM-CSF. The proportion of bone marrow megakaryocytes with a size less than 18 microns and greater than 35 microns resulted significantly higher in mice receiving rGM-CSF in comparison with controls; an increase in the percentage of splenic megakaryocytes greater than 35 microns was also observed. A statistically significant increase in the total spleen content of CFU-Meg was observed after administration of 90,000 and 120,000 U rGM-CSF three times a day for 6 days, while no effect on bone marrow CFU-Meg was recorded, irrespective of the dose delivered. Finally, 24 hours after a single intravenous injection of rGM-CSF, there was a significant increase in the proportion of CFU-Meg in S- phase, with the splenic progenitors being more sensitive than bone marrow-derived CFU-Meg. These data indicate that rGM-CSF has in vivo megakaryocyte stimulatory activity, and are consistent with previous in vitro observations. However, an effective stimulation of megakaryocytopoiesis in vivo, bringing about an increase in the levels of blood platelets, may require interaction of rGM-CSF with other cytokines.

Identification of tyrosine 706 in the kinase insert as the major colony-stimulating factor 1 (CSF-1)-stimulated autophosphorylation site in the CSF-1 receptor in a murine macrophage cell line

1990 ◽  
Vol 10 (6) ◽  
pp. 2991-3002
Author(s):  
P van der Geer ◽  
T Hunter
Keyword(s):  
Cell Line ◽  
Murine Macrophage ◽  
Colony Stimulating Factor ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Major Site ◽  
Murine Macrophage Cell Line ◽  
Stimulating Factor

The receptor for colony-stimulating factor 1 (CSF-1) is a ligand-activated protein-tyrosine kinase. It has been shown previously that the CSF-1 receptor is phosphorylated on serine in vivo and that phosphorylation on tyrosine can be induced by stimulation with CSF-1. We studied the phosphorylation of the CSF-1 receptor by using the BAC1.2F5 murine macrophage cell line, which naturally expresses CSF-1 receptors. Two-dimensional tryptic phosphopeptide mapping showed that the CSF-1 receptor is phosphorylated on several different serine residues in vivo. Stimulation with CSF-1 at 37 degrees C resulted in rapid phosphorylation on tyrosine at one major site and one or two minor sites. We identified the major site as Tyr-706. The identity of Tyr-706 was confirmed by mutagenesis. This residue is located within the kinase insert domain. There was no evidence that Tyr-973 (equivalent to Tyr-969 in the human CSF-1 receptor) was phosphorylated following CSF-1 stimulation. When cells were stimulated with CSF-1 at 4 degrees C, additional phosphotyrosine-containing phosphopeptides were detected and the level of phosphorylation of the individual phosphotyrosine-containing phosphopeptides was substantially increased. In addition, we show that CSF-1 receptors are capable of autophosphorylation at six to eight major sites in vitro.

scholarly journals A comparison of hematopoiesis in normal and splenectomized mice treated with granulocyte colony-stimulating factor

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 563-569 ◽  
Author(s):  
G Molineux ◽  
Z Pojda ◽  
TM Dexter
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Extramedullary Hematopoiesis ◽  
High Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Response Data ◽  
Hematopoietic Precursor ◽  
Stimulating Factor

Abstract Recombinant human granulocyte colony-stimulating factor (rhG-CSF) induces leukocytosis in vivo in both intact and splenectomized mice. Full dose response data showed a plateau in this effect at doses over 500 micrograms rhG-CSF/kg body weight/d in intact mice. The effect is magnified in splenectomized mice, where leukocyte numbers reach 100 x 10(6) mL after 4 days' treatment at 250 micrograms/kg/d. Further hematopoietic precursor populations are also affected in both marrow and the spleen; in general, marrow parameters were depressed, while splenic populations were enlarged. In splenectomized mice, both blood- borne stem cells were enhanced, and foci of extramedullary hematopoiesis were enlarged in addition to the effects seen in intact mice. In the marrow of splenectomized and intact mice treated with a high dose of G-CSF, erythroid suppression in the marrow was confirmed with radioactive iron. Our studies confirm and extend previous work on the mode of action of G-CSF, and indicate that side effects of high dose G-CSF therapy might include erythroid suppression in the bone marrow.

scholarly journals 735 Identification of a small molecule that prevents T cell exhaustion using machine learning algorithms paired with high-resolution single cell RNAseq

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A766-A766
Author(s):  
Isabelle Le Mercier ◽  
Sunny Sun ◽  
Dongmei Xiao ◽  
Laura Isacco ◽  
Daniel Treacy ◽  
...  
Keyword(s):  
T Cell ◽  
Low Dose ◽  
Machine Learning Algorithms ◽  
High Dose ◽  
T Cell Exhaustion ◽  
Tcr Signaling ◽  
Compound A ◽  
Cell Exhaustion

BackgroundT cell responses are tightly regulated and require a constant balance of signals during the different stages of their activation, expansion, and differentiation. As a result of chronic antigen exposure, T cells become exhausted in solid tumors, preventing them from controlling tumor growth.MethodsWe identified a transcriptional signature associated with T cell exhaustion in patients with melanoma and used our proprietary machine learning algorithms to predict molecules that would prevent T cell exhaustion and improve T cell function. Among the predictions, an orally available small molecule, Compound A, was highly predicted.ResultsCompound A was tested in an in vitro T cell Exhaustion assay and shown to prevent loss of proliferation and expression of immune checkpoint receptors. Transcriptionally, Compound A-treated cells looked indistinguishable from conventionally expanded, non-exhausted T cells. However, when assessed in a classical T cell activation assay, Compound A demonstrated dose dependent activity. At low dose, Compound A was immuno-stimulatory, allowing cells to divide further by preventing activation induced cell death. At higher doses, Compound A demonstrated immuno-suppressive activity preventing early CD69 upregulation and T cell proliferation. All together, these observations suggest that Compound A prevented exhaustion with a mechanism of action involving TCR signaling inhibition. While cessation of TCR signaling or rest has been recently associated with improved CAR-T efficacy by preventing or reversing exhaustion during the in vitro manufacturing phase, it is unclear if that mechanism would translate in vivo.Compound A was evaluated in the CT26 and MC38 syngeneic mouse models alongside anti-PD1. At low dose Compound A closely recapitulated anti-PD1 mediated cell behavior changes by scRNA-seq and flow cytometry in CT26 mice. At high dose, Compound A led to the accumulation of naive cells in the tumor microenvironment (TME) confirming the proposed mechanism of action. Low dose treatment was ineffective in MC38 mouse model but a pulsed treatment at high dose also recapitulated anti-PD1 activity in most animals. Importantly, we identified a new T cell population responding to anti-PD1 that was particularly increased in the MC38 mouse model; Compound A treatment also impacted this population.ConclusionsThese data confirm that mild TCR inhibition either suboptimal or fractionated can prevent exhaustion in vivo. However, this approach has a very limited window of activity between immuno-modulatory and immuno-suppressive effects, thereby limiting potential clinical benefit. Finally, these results demonstrate that our approach and platform was able to predict molecules that would prevent T cell exhaustion in vivo.

scholarly journals Επικεκαλυμμένες ενδαγγειακές προθέσεις και επαναστένωση μετά από αγγειοπλαστική

2014 ◽  
Author(s):  
Δημήτριος Λυσίτσας
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Low Dose ◽  
High Dose ◽  
Hsp 70

Εισαγωγή: Η υπερπλασία του έσω χιτώνα παίζει μείζων ρόλο στην επαναστένωση (in-stentrestenosis). Στην παρούσα μελέτη αξιολογήσαμε in vitro την επίδραση της D-24851(κυτταροτοξική ουσία που σταματά τον κυτταρικό κύκλο στο στάδιο G2-M) στονπολλαπλασιασμό των λείων μυϊκών κυττάρων και μελετήσαμε την ασφάλεια και τηνδραστικότητα μίας ενδαγγειακής πρόθεσης (stent) επικαλυμμένης με πολυμερή ουσία πουαπελευθερώνει την D-24851, στην αναστολή της υπερπλασίας του έσω χιτώνα χωρίς ναεμποδίζει την αναγεννητική ικανότητα του ενδοθηλίου σε in vivo πειραματικό μοντέλο.Υλικό και Μέθοδοι: Γυμνά μεταλλικά stent (n=6), stent επικαλυμμένα μόνο με πολυμερήουσία (polymer-coated, n=7) και stent επικαλυμμένα με πολυμερή ουσία πουαπελευθερώνουν 31±1μg (low-dose, n=7), 216±8 μg (high-dose, n=6) ή 1774±39 μg(extreme-dose, n=5) της D-24851 εμφυτεύτηκαν στις μηριαίες αρτηρίες λευκών New Zealandκουνελιών. Τα πειραματόζωα θυσιάστηκαν στις 28 ημέρες για ιστομορφομετρική ανάλυση.Για την αξιολόγηση της ενδοθηλιακής αναγέννησης στις 90 ημέρες, 12 πειραματόζωαχρησιμοποιήθηκαν για την τοποθέτηση polymer-coated (n=3), low dose (n=3), high dose(n=3) or extreme dose (n=3) ενδαγγειακών προθέσεων.Αποτελέσματα: In vitro η D-24851 αναστέλλει την υπερπλασία των λείων μυϊκών κυττάρωνκαι επάγει την απόπτωση τους χωρίς να αυξάνει την επαγωγή της heat shock protein 70(HSP-70), μία κυτταροπροστατευτική και αντι-αποπτωτική πρωτεΐνη. Η θεραπεία με lowdoseD-24851 stents συνδυάστηκε με 38% (P=0.029) μείωση της υπερπλαστικής περιοχήςτου έσω χιτώνα και 35% (P=0.003) μείωση της επι τοις εκατό στένωσης του αυλού σεσύγκριση με τα γυμνά μεταλλικά stents. Ο τραυματισμός και η φλεγμονή του αρτηριακού τοιχώματος δεν παρουσίασαν σημαντικές διαφορές μεταξύ των ομάδων. Τα επικαλυμμέναμόνο με πολυμερή ουσία stents εμφάνισαν παρόμοια ανάπτυξη νεοιστού σε σύγκριση με ταγυμνά μεταλλικά stents. Ωστόσο, όλες οι ομάδες των stents με D-24851 παρουσίασαν ατελήενδοθηλιοποίηση συγκρινόμενα με τα polymer-coated stents.Συμπεράσματα: Οι επικεκαλυμμένες ενδαγγειακές προσθέσεις με πολυμερή ουσία καιχαμηλη δόση D-24851 μειώνουν σημαντικά την υπερπλασιά του έσω χιτώνα. Λόγω τηςατελούς ενδοθηλιοποίησης, μακράς διάρκειας μελέτες είναι απαραίτητες για ναπιστοποιήσουν ότι η αναστολή του νεοιστού παραμένει και μετά τις 28 ημέρες.

scholarly journals In Vivo Administration of Granulocyte Colony-Stimulating Factor Increases the Immune Effectiveness of Dendritic Cell-Based Cancer Vaccination

2019 ◽  
Author(s):  
Shigetaka Shimodaira ◽  
Ryu Yanagisawa ◽  
Terutsugu Koya ◽  
Koichi Hirabayashi ◽  
Yumiko Higuchi ◽  
...  
Keyword(s):  
Low Dose ◽  
Immune Monitoring ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Functional Activities ◽  
Pulsed Dc ◽  
Dc Vaccines ◽  
Stimulating Factor ◽  
Autologous Monocyte

Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16–18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.

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