scholarly journals The Potential Role of Recombinant Hematopoietic Colony-Stimulating Factors in Preventing Infections in the Immunocompromised Host

1991 ◽  
Vol 2 (2) ◽  
pp. 74-88 ◽  
Author(s):  
James Rusthoven
Keyword(s):  
Bone Marrow ◽  
Interleukin 1 ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cell Recovery ◽  
Colony Stimulating Factors ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor

Hematopoietic colony-stimulating factors coordinate the proliferation and maturation of bone marrow and peripheral blood cells during normal hematopoiesis. Most of these factors are now available as recombinant human colony-stimulating factors, and preclinical and clinical testing is proceeding rapidly. Granulocyte and granulocyte/macrophage colony-stimulating factors have been the most extensively studied to date. In human clinical trials, granulocyte colony-stimulating factor improves neutrophil counts and function, reduces episodes of febrile neutropenia, improves neutrophil recovery after disease- or treatment-induced myelosuppression, and reduces the number of serious infections in several neutropenic disease states. Granulocyte/macrophage colony-stimulating factor has similar biological properties but may also improve eosinophil proliferation and function, and platelet cell recovery after myelotoxic bone marrow injury, Interleukin-1 boosts the effects of granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor, but also may promote the resolution of established infections in conjunction with antibiotics. The therapeutic realities and future therapeutic implications of these agents for the therapy of infections, cancer and hemopoietic disorders are discussed.

scholarly journals In vivo administration of recombinant human interleukin-1 and macrophage colony-stimulating factor (M-CSF) induce a rapid loss of M- CSF receptors in mouse bone marrow cells and peritoneal macrophages: effect of administration route

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1923-1928 ◽  
Author(s):  
BD Chen
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
In Vivo Administration ◽  
Stimulating Factor ◽  
Marrow Cells

Abstract Earlier studies suggested the existence of a blood-bone marrow barrier that significantly inhibits the transfer of plasma macrophage colony- stimulating factor (M-CSF) to responsive hematopoietic cells in vivo as indicated by its failure to induce a receptor downregulation in bone marrow cells. In this study, the effect of recombinant human interleukin-1 (rhuIL-1) was investigated. In vivo administration of rhuIL-1, either intraperitoneally (IP) or intravenously (IV), induced a rapid transient loss of M-CSF receptor binding activity in bone marrow cells, with a nadir occurring between 2 to 4 hours while loss of M-CSF receptors by cells in the peritoneal cavity occurred only in animals receiving rhuIL-1 via IP administration. The loss of M-CSF receptor activity after rhuIL-1 treatment was correlated with an elevated level of circulating M-CSF. However, the loss of M-CSF receptors in marrow cells was prevented by dexamethasone (Dex) treatment before rhuIL-1 administration. The fact that Dex treatment also reduced the level of circulating M-CSF after rhuIL-1 administration suggests that the inhibitory effects of IL-1 are mediated through locally produced M-CSF. Administration of rhuM-CSF at higher doses, either IV or IP, also induced a loss of M-CSF receptor of lesser degree in the marrow cells. However, the loss of M-CSF receptors by the peritoneal cells was induced only in mice receiving rhuM-CSF through IP administration. Taken together, these results indicate the existence of a unidirectional barrier that prevents the transfer of blood M-CSF and IL- 1 to peritoneal cavity but not vice versa.

scholarly journals In vivo administration of recombinant human interleukin-1 and macrophage colony-stimulating factor (M-CSF) induce a rapid loss of M- CSF receptors in mouse bone marrow cells and peritoneal macrophages: effect of administration route

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1923-1928
Author(s):  
BD Chen
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
In Vivo Administration ◽  
Stimulating Factor ◽  
Marrow Cells

Earlier studies suggested the existence of a blood-bone marrow barrier that significantly inhibits the transfer of plasma macrophage colony- stimulating factor (M-CSF) to responsive hematopoietic cells in vivo as indicated by its failure to induce a receptor downregulation in bone marrow cells. In this study, the effect of recombinant human interleukin-1 (rhuIL-1) was investigated. In vivo administration of rhuIL-1, either intraperitoneally (IP) or intravenously (IV), induced a rapid transient loss of M-CSF receptor binding activity in bone marrow cells, with a nadir occurring between 2 to 4 hours while loss of M-CSF receptors by cells in the peritoneal cavity occurred only in animals receiving rhuIL-1 via IP administration. The loss of M-CSF receptor activity after rhuIL-1 treatment was correlated with an elevated level of circulating M-CSF. However, the loss of M-CSF receptors in marrow cells was prevented by dexamethasone (Dex) treatment before rhuIL-1 administration. The fact that Dex treatment also reduced the level of circulating M-CSF after rhuIL-1 administration suggests that the inhibitory effects of IL-1 are mediated through locally produced M-CSF. Administration of rhuM-CSF at higher doses, either IV or IP, also induced a loss of M-CSF receptor of lesser degree in the marrow cells. However, the loss of M-CSF receptors by the peritoneal cells was induced only in mice receiving rhuM-CSF through IP administration. Taken together, these results indicate the existence of a unidirectional barrier that prevents the transfer of blood M-CSF and IL- 1 to peritoneal cavity but not vice versa.

In Vitro Expansion of CD34+ Cells Mobilized with Chemotherapy and G-CSF

1993 ◽  
Vol 16 (5_suppl) ◽  
pp. 89-95 ◽  
Author(s):  
L. Teofili ◽  
M.S. Iovino ◽  
A. Di Mario ◽  
E. Ortu La Barbera ◽  
L. Pierelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Adherent Cell ◽  
Colony Stimulating Factor ◽  
Cell Recovery ◽  
Gm Csf ◽  
Cd34 Cells ◽  
Macrophage Colony ◽  
Stimulating Factor

Hemopoietic CD34+ progenitors were isolated by immunomagnetic method from normal bone marrow (BM) or from peripheral blood (PB) of patients with non-Hodgkin's lymphoma treated with chemotherapy and granulocyte colony-stimulating factor (GCSF). Aliquots were seeded in longterm cultures (LTC) on bone marrow-derived stromal layers; non-adherent and adherent clonogenic content of the cultures was assayed weekly. The final recovery and the clonogenic efficiency of the CD34+ cells were sligthly higher in PB samples than in BM controls. In long term cultures PB cells sustained hemopoiesis as much as BM cells; at week 3 and 4 PB total mononuclear cells and CD34+ cells showed a non-adherent cell recovery higher than the respective BM controls. Furthermore, PB CD34+ cells were expanded in liquid culture in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF alone or combined with interleukin 3 (IL3), stem cell factor (SCF), interleukin 1 (IL 1), interleukin 6 (IL6). The combination of GM-CSF, IL3, SCF, IL 1 and IL6 produced the maximum increase of both mononuclear cells (30-fold) and granulocyte-macrophage colony forming units (CFU-GM) (4.6-fold) after 7 days of cultures; yet after 14 days a strong decrease of the CFU-GM occurred. These data suggest that G-CSF following chemotherapy mobilizes both early and committed hemopoietic progenitors.

scholarly journals Hematopoietic precursors resistant to treatment with 4- hydroperoxycyclophosphamide: requirement for an interaction with marrow stroma in addition to hematopoietic growth factors for maximal generation of colony-forming activity

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 60-65 ◽  
Author(s):  
SD Rowley ◽  
C Brashem-Stein ◽  
R Andrews ◽  
ID Bernstein
Keyword(s):  
Growth Factors ◽  
Cell Layer ◽  
Interleukin 1 ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Marrow Stroma ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

We tested the ability of CD34+lin- precursor cells isolated from marrow after treatment with 4-hydroperoxycyclophosphamide (4HC) to generate colony-forming cells (CFC). In liquid cultures, recombinant human stem cell factor (SCF), in combination with interleukin-1 (IL-1), IL-3, IL- 6, granulocyte-macrophage colony-stimulating factor, or granulocyte colony-stimulating factor caused untreated, but not 4HC-treated, CD34+lin- cells to form CFC. However, generation of CFC from CD34+lin- cells treated with 60 micrograms/mL of 4HC was possible in the presence of an irradiated allogeneic stromal cell layer. This generation was increased when combinations of hematopoietic growth factors including SCF and IL-3 were added. Maximal generation of CFC was seen after 11 to 21 days of culture. At that time, generation of CFC from CD34+lin- 4HC- treated cells equalled that from untreated cells. The phenotype of these 4HC-resistant CD34+lin- precursors was also further defined as CD38-. These studies show that the generation of CFC from the 4HC- resistant, highly immature population of CD34+lin- cells requires an as yet undefined interaction with marrow stroma in addition to known hematopoietic growth factors.

scholarly journals Expression and function of the human granulocyte-macrophage colony- stimulating factor receptor alpha subunit

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4174-4185 ◽  
Author(s):  
PT Jubinsky ◽  
AS Laurie ◽  
DG Nathan ◽  
J Yetz-Aldepe ◽  
CA Sieff
Keyword(s):  
Bone Marrow ◽  
Normal Bone Marrow ◽  
Colony Stimulating Factor ◽  
Receptor Alpha ◽  
Gm Csf ◽  
Normal Bone ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor

To determine the expression and function of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha chain (GMR alpha) during hematopoiesis and on leukemic cells, monoclonal antibodies were raised by immunizing mice with cells expressing high levels of human GMR alpha. A pool of five antibodies isolated from three different mice was used to characterize GMR alpha. This antibody pool (anti-GMR alpha) immunoprecipitated a protein with the expected molecular weight of GMR alpha from COS cells transiently transfected with the GMR alpha gene. In factor-dependent cells, GMR alpha existed as a phosphoprotein. However, its phosphorylation was not stimulated by the presence of GM- CSF. Anti-GMR alpha inhibited the GM-CSF-dependent growth of cell lines and normal bone marrow cells and inhibited the binding of iodinated GM- CSF to its receptor. Cell surface expression of GMR alpha was examined using anti-GMR alpha and flow cytometry. GMR alpha was readily detectable on both blood monocytes and neutrophils. In adherence- depleted normal bone marrow, two separate populations expressed GMR alpha. The most positive cells were predominantly macrophages, whereas the cells that expressed less GMR alpha were largely myelocytes and metamyelocytes. A small population of lin-CD34+ or CD34+CD38- cells also expressed GMR alpha, but they were not capable of significant growth in colony-forming assays. In contrast, the majority of lin-CD34+ and CD34+CD38- cells were GMR alpha-, yet they produced large numbers of myeloid and erythroid colonies in the same assay. Malignant cells from patients with leukemia were also tested for GMR alpha expression. All of the myeloid leukemias and only rare lymphoid leukemias surveyed tested positive for GMR alpha. These results show that anti-GMR alpha is useful for the functional characterization of the GMR alpha and for the detection of myeloid leukemia and that GMR alpha is expressed on certain lineages throughout hematopoietic development; however, progenitors that express the receptor may have a reduced capacity to proliferate in response to hematopoietic growth factors.

scholarly journals Quantitative cell-cycle progression analysis of the first three successive cell cycles of granulocyte colony-stimulating factor and/or granulocyte-macrophage colony-stimulating factor-stimulated human CD34+ bone marrow cells in relation to their colony formation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3211-3216 ◽  
Author(s):  
F Lardon ◽  
DR Van Bockstaele ◽  
HW Snoeck ◽  
ME Peetermans
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Target Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cell Cycles ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The bromodeoxyuridine (BrdU)-Hoechst flow cytometric technique was applied to study the immediate cell kinetic response of highly purified human (h) bone marrow progenitor cells (CD(34+)-sorted fraction) to h granulocyte colony-stimulating factor (G-CSF) and/or h granulocyte- macrophage colony-stimulating factor (GM-CSF). The technique permits us to differentiate cycling from noncycling cells and to make a quantitative assessment of cell cycles after stimulation. Semisolid agar and single-cell liquid cultures were also performed to compare these initial events to the effects observed after 14 days of culture. The combination of G-CSF plus GM-CSF, acting synergistically in day 14 cultures, was found to have a subadditive effect in the first cell cycles, thereby indicating partial overlap of the different target cells. However, this combination accelerated transit through the cell cycle, as could be seen from the higher number of cells in the third cell cycle after 72 hours of stimulation. We conclude that, apart from the unresponsive cells, the CD34+ compartment consists of cells responsive to both G-CSF and GM-CSF, and cells responsive to either one of the CSFs alone, and that the combination of the two CSFs speeds up the cell cycle traverse rate for a significant fraction of the target cells that are initially responsive for both G-CSF and GM-CSF. The latter supports the hypothesis of an overlapping signalling pathway of G-CSF and GM-CSF.

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