scholarly journals Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease

2021 ◽  
Author(s):  
Sahar Keshvari ◽  
Berit Genz ◽  
Ngari Teakle ◽  
Melanie Caruso ◽  
Michelle F Cestari ◽  
...  
Keyword(s):  
Liver Disease ◽  
Therapeutic Potential ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Colony Stimulating Factor ◽  
Liver Growth ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Impact ◽  
Stimulating Factor

Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to TAA exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.

scholarly journals Characterization of the clinical effects after the first dose of bacterially synthesized recombinant human granulocyte-macrophage colony- stimulating factor

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2634-2643 ◽  
Author(s):  
GJ Lieschke ◽  
J Cebon ◽  
G Morstyn
Keyword(s):  
Therapeutic Potential ◽  
Chest Roentgenogram ◽  
Arterial Oxygen ◽  
Clinical Effects ◽  
Colony Stimulating Factor ◽  
Single Breath ◽  
Prolonged Duration ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Bacterially synthesized recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS).

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor inStaphylococcus aureus-Induced Arthritis

1998 ◽  
Vol 66 (2) ◽  
pp. 853-855 ◽  
Author(s):  
Margareta Verdrengh ◽  
Andrej Tarkowski
Keyword(s):  
Tissue Injury ◽  
Favorable Effect ◽  
Protective Effects ◽  
Colony Stimulating Factor ◽  
Bacterial Inoculation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Impact ◽  
Stimulating Factor

ABSTRACT Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is able to increase not only the production of phagocytic cells but also their efficacy with respect to, e.g., bactericidal properties. In this study, we wanted to analyze the impact of GM-CSF on experimental Staphylococcus aureus-induced arthritis. For that purpose, mice were administered GM-CSF before and after bacterial inoculation. Although there was an increase in the total number of leukocytes as well as in the granulocyte fraction, there was no favorable effect on the severity of arthritis or on survival rates. There were no obvious differences between the GM-CSF-pretreated animals and controls with regard to growth of staphylococci in joints and kidneys 4 days after the bacterial inoculation. In contrast, mice that had been pretreated with GM-CSF prior to bacterial inoculation showed approximately four times lower numbers of bacteria in their blood 24 h later. These results, along with those of our previous studies, suggest that on the one hand the granulocyte is the main protective cell during the course of S. aureus infection but that on the other hand, upregulation of granulocyte-macrophage production will not exert any additional protective effects with respect to tissue injury.

Recombinant human granulocyte-macrophage colony-stimulating factor as an adjunct to conventional-dose ifosfamide-based chemotherapy for patients with advanced or relapsed germ cell tumors: a randomized trial.

1995 ◽  
Vol 13 (1) ◽  
pp. 79-86 ◽  
Author(s):  
D F Bajorin ◽  
C R Nichols ◽  
H J Schmoll ◽  
P W Kantoff ◽  
C Bokemeyer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Infectious Complications ◽  
Colony Stimulating Factor ◽  
Routine Administration ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Impact ◽  
Stimulating Factor

PURPOSE Ifosfamide-containing therapy with cisplatin plus either etoposide (VIP) or vinblastine (VeIP) can cure of patients with relapsed germ cell tumors (GCTs), but results in substantial myelotoxicity. This study sought to assess the impact of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on the severity of neutropenia and incidence of infectious complications in patients who receive ifosfamide-based chemotherapy for GCT. PATIENTS AND METHODS One hundred and four assessable GCT patients from 20 centers were randomized to receive rhGM-CSF with either cycles 1 and 2 or cycles 3 and 4 of chemotherapy. Standard doses of VIP or VeIP were used. Efficacy data were analyzed using a parallel design for cycles 1 and 2 before the crossover. RESULTS Fewer clinically relevant infections occurred in rhGM-CSF patients (13 of 55, 24%) versus observation patients (22 of 49, 45%) in cycle 1 (P = .01). Decreases were observed in infections during neutropenia (22% v 43%, P = .03), infections requiring intravenous antibiotics (20% v 43%, P = .01), and any infection irrespective of severity (29% v 55%, P = .01) in cycle 1. However, there were no significant differences among the treatment arms in cycle 2 in the proportion of clinically relevant infections (P = .23), infections associated with neutropenia (P = .11), infections requiring antibiotics (P = .22), or any infection (P = .65). rhGM-CSF was discontinued in 14% of cycles because of toxicity related to the growth factor. CONCLUSION rhGM-CSF reduced the incidence of infections in the first cycle of chemotherapy, but no benefit beyond the initial chemotherapy cycle was evident. Based on the limited clinical impact and the high incidence of rhGM-CSF-related toxicity that required growth factor discontinuation, the routine administration of rhGM-CSF to prevent neutropenia and infection after ifosfamide-based chemotherapy for GCT patients is not recommended.

Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level.

1992 ◽  
Vol 10 (8) ◽  
pp. 1266-1277 ◽  
Author(s):  
S Vadhan-Raj ◽  
H E Broxmeyer ◽  
W N Hittelman ◽  
N E Papadopoulos ◽  
S P Chawla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Schedule ◽  
Severe Neutropenia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Impact ◽  
Stimulating Factor ◽  
Modified Schedule

PURPOSE The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma. PATIENTS AND METHODS Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined. RESULTS In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated, By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P less than .01 and P less than .001). The duration of severe neutropenia (neutrophil count less than 500/mm3) and myeloid leukopenia (myeloid leukocyte count less than 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P less than .001). While 16 of 17 patients experienced severe myeloid leukopenia (less than 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P less than .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation. CONCLUSIONS The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.

scholarly journals Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs

2016 ◽  
Vol 311 (3) ◽  
pp. G533-G547 ◽  
Author(s):  
Kristin A. Sauter ◽  
Lindsey A. Waddell ◽  
Zofia M. Lisowski ◽  
Rachel Young ◽  
Lucas Lefevre ◽  
...  
Keyword(s):  
Steady State ◽  
Hepatocyte Proliferation ◽  
Hepatic Regeneration ◽  
Colony Stimulating Factor ◽  
Blood Monocytes ◽  
Selective Enrichment ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
State Size ◽  
Stimulating Factor

Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the role of CSF1 in steady-state control of monocyte production and differentiation and tissue repair, we previously developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with the Fc region of pig IgG1a. CSF1-Fc administration to pigs expanded progenitor pools in the marrow and selectively increased monocyte numbers and their expression of the maturation marker CD163. There was a rapid increase in the size of the liver, and extensive proliferation of hepatocytes associated with increased macrophage infiltration. Despite the large influx of macrophages, there was no evidence of liver injury and no increase in circulating liver enzymes. Microarray expression profiling of livers identified increased expression of macrophage markers, i.e., cytokines such as TNF, IL1, and IL6 known to influence hepatocyte proliferation, alongside cell cycle genes. The analysis also revealed selective enrichment of genes associated with portal, as opposed to centrilobular regions, as seen in hepatic regeneration. Combined with earlier data from the mouse, this study supports the existence of a CSF1-dependent feedback loop, linking macrophages of the liver with bone marrow and blood monocytes, to mediate homeostatic control of the size of the liver. The results also provide evidence of safety and efficacy for possible clinical applications of CSF1-Fc.

scholarly journals Mycobacterium tuberculosis replicates within necrotic human macrophages

2017 ◽  
Vol 216 (3) ◽  
pp. 583-594 ◽  
Author(s):  
Thomas R. Lerner ◽  
Sophie Borel ◽  
Daniel J. Greenwood ◽  
Urska Repnik ◽  
Matthew R.G. Russell ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Single Cell Analysis ◽  
Colony Stimulating Factor ◽  
Extracellular Milieu ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Bacterial Replication ◽  
Differential Ability ◽  
The Impact ◽  
Stimulating Factor

Mycobacterium tuberculosis modulation of macrophage cell death is a well-documented phenomenon, but its role during bacterial replication is less characterized. In this study, we investigate the impact of plasma membrane (PM) integrity on bacterial replication in different functional populations of human primary macrophages. We discovered that IFN-γ enhanced bacterial replication in macrophage colony-stimulating factor–differentiated macrophages more than in granulocyte–macrophage colony-stimulating factor–differentiated macrophages. We show that permissiveness in the different populations of macrophages to bacterial growth is the result of a differential ability to preserve PM integrity. By combining live-cell imaging, correlative light electron microscopy, and single-cell analysis, we found that after infection, a population of macrophages became necrotic, providing a niche for M. tuberculosis replication before escaping into the extracellular milieu. Thus, in addition to bacterial dissemination, necrotic cells provide first a niche for bacterial replication. Our results are relevant to understanding the environment of M. tuberculosis replication in the host.

scholarly journals Characterization of the clinical effects after the first dose of bacterially synthesized recombinant human granulocyte-macrophage colony- stimulating factor

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2634-2643 ◽  
Author(s):  
GJ Lieschke ◽  
J Cebon ◽  
G Morstyn
Keyword(s):  
Therapeutic Potential ◽  
Chest Roentgenogram ◽  
Arterial Oxygen ◽  
Clinical Effects ◽  
Colony Stimulating Factor ◽  
Single Breath ◽  
Prolonged Duration ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Bacterially synthesized recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS).

scholarly journals Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling

Blood ◽  
2012 ◽  
Vol 119 (8) ◽  
pp. 1810-1820 ◽  
Author(s):  
David A. Hume ◽  
Kelli P. A. MacDonald
Keyword(s):  
Tissue Repair ◽  
Therapeutic Potential ◽  
Macrophage Phenotype ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Multiple Levels ◽  
Macrophage Colony ◽  
Macrophage Populations ◽  
Adaptive Immune Systems ◽  
Stimulating Factor

AbstractMacrophage-colony stimulating factor (CSF-1) signaling through its receptor (CSF-1R) promotes the differentiation of myeloid progenitors into heterogeneous populations of monocytes, macrophages, dendritic cells, and bone-resorbing osteoclasts. In the periphery, CSF-1 regulates the migration, proliferation, function, and survival of macrophages, which function at multiple levels within the innate and adaptive immune systems. Macrophage populations elicited by CSF-1 are associated with, and exacerbate, a broad spectrum of pathologies, including cancer, inflammation, and bone disease. Conversely, macrophages can also contribute to immunosuppression, disease resolution, and tissue repair. Recombinant CSF-1, antibodies against the ligand and the receptor, and specific inhibitors of CSF-1R kinase activity have been each been tested in a range of animal models and in some cases, in patients. This review examines the potential clinical uses of modulators of the CSF-1/CSF-1R system. We conclude that CSF-1 promotes a resident-type macrophage phenotype. As a treatment, CSF-1 has therapeutic potential in tissue repair. Conversely, inhibition of CSF-1R is unlikely to be effective in inflammatory disease but may have utility in cancer.

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