scholarly journals Enhanced marrow recovery by short preincubation of marrow allografts with human recombinant interleukin-3 and granulocyte-macrophage colony- stimulating factor

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1673-1678 ◽  
Author(s):  
E Naparstek ◽  
Y Hardan ◽  
M Ben-Shahar ◽  
A Nagler ◽  
R Or ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Study Group ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Duration Of Hospitalization ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We studied an alternative method of using hematopoietic growth factors (HGFs) to enhance hematopoietic recovery in patients undergoing bone marrow transplantation (BMT), by short in vitro preincubation. Twenty consecutive patients with leukemia received T-cell-depleted allografts using Campath-1G. Two thirds of the marrow was infused on the scheduled day of transplant and one third of the marrow following preincubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) on day 4. Engraftment parameters and duration of hospitalization were compared by actuarial analysis to those of 40 historical controls. Patients receiving the incubated boost had significantly faster platelet recovery (P = .017) and shorter hospitalization period (P = .001) when compared with the control subjects. Platelet count reached greater than 25 x 10(9)/L on day 17 (median) in the study group and on day 23 in the controls. The median duration of hospitalization was 20 and 36 days, respectively. In the early posttransplantation follow-up, two of four patients in the study group died as a result of graft rejection, while all 13 deaths in the control group resulted from complications associated with marrow suppression. We suggest that pretransplant in vitro activation of bone marrow cells with IL-3 and GM-CSF may prove to be an efficient method for enhancing marrow recovery after BMT.

scholarly journals Enhanced marrow recovery by short preincubation of marrow allografts with human recombinant interleukin-3 and granulocyte-macrophage colony- stimulating factor

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1673-1678 ◽  
Author(s):  
E Naparstek ◽  
Y Hardan ◽  
M Ben-Shahar ◽  
A Nagler ◽  
R Or ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Study Group ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Duration Of Hospitalization ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

We studied an alternative method of using hematopoietic growth factors (HGFs) to enhance hematopoietic recovery in patients undergoing bone marrow transplantation (BMT), by short in vitro preincubation. Twenty consecutive patients with leukemia received T-cell-depleted allografts using Campath-1G. Two thirds of the marrow was infused on the scheduled day of transplant and one third of the marrow following preincubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) on day 4. Engraftment parameters and duration of hospitalization were compared by actuarial analysis to those of 40 historical controls. Patients receiving the incubated boost had significantly faster platelet recovery (P = .017) and shorter hospitalization period (P = .001) when compared with the control subjects. Platelet count reached greater than 25 x 10(9)/L on day 17 (median) in the study group and on day 23 in the controls. The median duration of hospitalization was 20 and 36 days, respectively. In the early posttransplantation follow-up, two of four patients in the study group died as a result of graft rejection, while all 13 deaths in the control group resulted from complications associated with marrow suppression. We suggest that pretransplant in vitro activation of bone marrow cells with IL-3 and GM-CSF may prove to be an efficient method for enhancing marrow recovery after BMT.

Bcr-Abl Efficiently Induces a Myeloproliferative Disease and Production of Excess Interleukin-3 and Granulocyte-Macrophage Colony-Stimulating Factor in Mice: A Novel Model for Chronic Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3829-3840 ◽  
Author(s):  
Xiaowu Zhang ◽  
Ruibao Ren
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Molecular Mechanisms ◽  
Myelogenous Leukemia ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The bcr-abl oncogene plays a critical role in causing chronic myelogenous leukemia (CML). Effective laboratory animal models of CML are needed to study the molecular mechanisms by which thebcr-abl oncogene acts in the disease progression of CML. We used a murine stem cell retroviral vector (MSCV) to transduce thebcr-abl/p210 oncogene into mouse bone marrow cells and found that expression of Bcr-Abl/p210 induced a myeloproliferative disorder that resembled the chronic phase of human CML in 100% of bone marrow transplanted mice in about 3 weeks. This CML-like disease was readily transplanted to secondary recipient mice. Multiple clones of infected cells were expanded in the primary recipients, but the leukemia was primarily monoclonal in the secondary recipient mice. Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Interestingly, we found that the leukemic cells expressed excess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the diseased mice. These studies demonstrate that expression of Bcr-Abl can induce a CML-like leukemia in mice much more efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cell(s). Our first use of this model for analysis of the molecular mechanisms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML.

Bcr-Abl Efficiently Induces a Myeloproliferative Disease and Production of Excess Interleukin-3 and Granulocyte-Macrophage Colony-Stimulating Factor in Mice: A Novel Model for Chronic Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3829-3840 ◽  
Author(s):  
Xiaowu Zhang ◽  
Ruibao Ren
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Molecular Mechanisms ◽  
Myelogenous Leukemia ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The bcr-abl oncogene plays a critical role in causing chronic myelogenous leukemia (CML). Effective laboratory animal models of CML are needed to study the molecular mechanisms by which thebcr-abl oncogene acts in the disease progression of CML. We used a murine stem cell retroviral vector (MSCV) to transduce thebcr-abl/p210 oncogene into mouse bone marrow cells and found that expression of Bcr-Abl/p210 induced a myeloproliferative disorder that resembled the chronic phase of human CML in 100% of bone marrow transplanted mice in about 3 weeks. This CML-like disease was readily transplanted to secondary recipient mice. Multiple clones of infected cells were expanded in the primary recipients, but the leukemia was primarily monoclonal in the secondary recipient mice. Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Interestingly, we found that the leukemic cells expressed excess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the diseased mice. These studies demonstrate that expression of Bcr-Abl can induce a CML-like leukemia in mice much more efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cell(s). Our first use of this model for analysis of the molecular mechanisms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML.

scholarly journals Recombinant human macrophage colony-stimulating factor (M-CSF) requires subliminal concentrations of granulocyte/macrophage (GM)-CSF for optimal stimulation of human macrophage colony formation in vitro.

1987 ◽  
Vol 166 (6) ◽  
pp. 1851-1860 ◽  
Author(s):  
D Caracciolo ◽  
N Shirsat ◽  
G G Wong ◽  
B Lange ◽  
S Clark ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Colony Formation ◽  
Human Macrophage ◽  
Colony Stimulating Factor ◽  
Colony Assay ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Human macrophage colony-stimulating factor (M-CSF or CSF-1), either in purified or in recombinant form, is able to generate macrophagic colonies in a murine bone marrow colony assay, but only stimulates small macrophagic colonies of 40-50 cells in a human bone marrow colony assay. We report here that recombinant human granulocytic/macrophage colony stimulating factor (rhGM-CSF) at concentrations in the range of picograms enhances the responsiveness of bone marrow progenitors to M-CSF activity, resulting in an increased number of macrophagic colonies of up to 300 cells. Polyclonal antiserum against M-CSF did not alter colony formation of bone marrow progenitors incubated with GM-CSF at optimal concentration (1-10 ng/ml) for these in vitro assays. Thus, GM-CSF at higher concentrations (nanogram range) can by itself, elicit macrophagic colonies, and at lower concentrations (picogram range) acts to enhance the responsiveness of these progenitors to M-CSF.

scholarly journals A comparison of treatment of canine cyclic hematopoiesis with recombinant human granulocyte-macrophage colony-stimulating factor (GM- CSF), G-CSF interleukin-3, and canine G-CSF

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 523-532 ◽  
Author(s):  
WP Hammond ◽  
TC Boone ◽  
RE Donahue ◽  
LM Souza ◽  
DC Dale
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Cell Counts ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Cyclic Hematopoiesis ◽  
Stimulating Factor

Cyclic hematopoiesis in gray collie dogs is a stem cell disease in which abnormal regulation of cell production in the bone marrow causes cyclic fluctuations of blood cell counts. In vitro studies demonstrated that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and granulocyte colony stimulating factor (G-CSF) all stimulated increases in colony formation by canine bone marrow progenitor cells. Based on these results, gray collie dogs were then treated with recombinant human (rh) GM-CSF, IL-3, or G-CSF subcutaneously to test the hypothesis that pharmacologic doses of one of these hematopoietic growth factors could alter cyclic production of cells. When recombinant canine G-CSF became available, it was tested over a range of doses. In vivo rhIL-3 had no effect on the recurrent neutropenia but was associated with eosinophilia, rhGM-CSF caused neutrophilia and eosinophilia but cycling of hematopoiesis persisted. However, rhG-CSF caused neutrophilia, prevented the recurrent neutropenia and, in the two animals not developing antibodies to rhG- CSF, obliterated periodic fluctuation of monocyte, eosinophil, reticulocyte, and platelet counts. Recombinant canine G-CSF increased the nadir neutrophil counts and amplitude of fluctuations at low doses (1 micrograms/kg/d) and eliminated all cycling of cell counts at high doses (5 and 10 micrograms/kg/d). These data suggest significant differences in the actions of these growth factors and imply a critical role for G-CSF in the homeostatic regulation of hematopoiesis.

scholarly journals Granulocyte-macrophage colony-stimulating factor-induced antibody- dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3474-3479 ◽  
Author(s):  
BS Charak ◽  
R Agah ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Cellular Cytotoxicity ◽  
Colony Stimulating Factor ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to induce antitumor activity in peripheral blood monocytes. We examined the role of GM-CSF on bone marrow (BM) macrophages in inducing antibody-dependent cellular cytotoxicity (ADCC) against murine and human tumor cells in vitro and in vivo with the aim of applying this approach in an autologous bone marrow transplantation (BMT) setting. GM- CSF induced a potent ADCC in BM macrophages against a murine melanoma in vitro. Treatment with GM-CSF alone or with antibody alone had no effect, whereas therapy with combination of both these agents resulted in a significant reduction in dissemination of melanoma both in a nontransplant as well as in BMT settings, with results being more optimal in the latter setting. Adoptive transfer of BM macrophages harvested from mice undergoing therapy with GM-CSF plus antibody significantly reduced the dissemination of melanoma in secondary recipients but only after irradiation, not in intact mice. GM-CSF also induced significant ADCC in human BM macrophages against a melanoma and a lymphoma in vitro and against a lymphoma implanted in nude mice in vivo. Again, these effects were more optimal after chemotherapy. These data suggest that treatment with GM-CSF plus tumor-specific monoclonal antibodies after BMT may induce an antitumor effect and help eradicate the minimal residual disease.

scholarly journals Differential effects of sequential, simultaneous, and single agent interleukin-3 and granulocyte-macrophage colony-stimulating factor on megakaryocyte maturation and platelet response in primates

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2479-2485 ◽  
Author(s):  
CP Stahl ◽  
EF Winton ◽  
MC Monroe ◽  
E Haff ◽  
RC Holman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Agent ◽  
Colony Stimulating Factor ◽  
Platelet Response ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) following interleukin-3 (IL-3) priming has been shown to increase thrombopoiesis. To elucidate the comparative abilities of IL-3 and GM- CSF in influencing megakaryocyte development in vivo, serial bone marrow analyses were performed on rhesus monkeys treated with 5 micrograms/kg/d of IL-3 and 5 micrograms/kg/d of GM-CSF sequentially for 4 days each, simultaneously for 8 days, and as single agents for 8 days. Platelet counts maximally increased to a mean of 7.5 x 10(5)/microL (n = 3) on days 11 through 12 in monkeys treated with sequential IL-3/GM-CSF. In contrast, neither IL-3 alone nor simultaneously administered IL-3/GM-CSF elicited increases in thrombopoiesis between days 3 and 15. GM-CSF elicited a variable platelet response. Megakaryocyte ploidy distributions were significantly (P < .001) shifted between days 7 and 10 in monkeys treated sequentially and between days 3 and 15 in monkeys treated with combined IL-3/GM-CSF and with GM-CSF alone but not in monkeys treated with IL-3 alone. The changes in mean DNA content and megakaryocyte size, as determined by digital image analysis, were larger in monkeys treated with sequential IL-3/GM-CSF and with GM-CSF alone than in simultaneously treated monkeys. In addition, sequentially but not simultaneously treated monkeys showed increased numbers of megakaryocytes on bone marrow biopsy. We conclude that administration of IL-3 followed by GM-CSF treatment increases thrombopoiesis by sequentially increasing megakaryocyte numbers and maturation and that these effects are diminished by simultaneous administration of the two cytokines.

scholarly journals Diamond-Blackfan anemia: promotion of marrow erythropoiesis in vitro by recombinant interleukin-3

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1168-1174 ◽  
Author(s):  
DS Halperin ◽  
Z Estrov ◽  
MH Freedman
Keyword(s):  
Bone Marrow ◽  
Dose Response ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Diamond Blackfan Anemia ◽  
Corrective Effect ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract To clarify the defective erythropoiesis in eight patients with Diamond- Blackfan anemia, we studied their bone marrow response in vitro to recombinant human interleukin-3 (IL-3) and recombinant granulocyte- macrophage colony-stimulating factor (GM-CSF). In an erythropoietin- containing assay system, specimens from six of the eight patients yielded low numbers of erythroid colonies compared to control values, and in five of these no erythropoietin dose-response could be elicited. Addition of IL-3, GM-CSF or both to cultures from the six patients had no effect on CFU-E-derived colonies. In contrast, IL-3 but not GM-CSF induced a marked increase in the number (183%) and size of the BFU-E- derived colonies in five of the six cases and partially corrected the impaired dose-response to erythropoietin in four. Bone marrow from the other two patients yielded numbers of CFU-E and BFU-E colonies comparable to controls and manifested similar increments in colonies with increasing concentrations of erythropoietin. When IL-3 was added to these cultures, further increments were observed in the number and size of BFU-E colonies. We conclude that IL-3 enhanced the marrow erythropoiesis in most of the patients and exerted a corrective effect on the aberrant colony formation in the presence of erythropoietin. The data raise the possibility of IL-3 as a therapeutic agent in Diamond- Blackfan anemia.

scholarly journals Diamond-Blackfan anemia: promotion of marrow erythropoiesis in vitro by recombinant interleukin-3

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1168-1174 ◽  
Author(s):  
DS Halperin ◽  
Z Estrov ◽  
MH Freedman
Keyword(s):  
Bone Marrow ◽  
Dose Response ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Diamond Blackfan Anemia ◽  
Corrective Effect ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

To clarify the defective erythropoiesis in eight patients with Diamond- Blackfan anemia, we studied their bone marrow response in vitro to recombinant human interleukin-3 (IL-3) and recombinant granulocyte- macrophage colony-stimulating factor (GM-CSF). In an erythropoietin- containing assay system, specimens from six of the eight patients yielded low numbers of erythroid colonies compared to control values, and in five of these no erythropoietin dose-response could be elicited. Addition of IL-3, GM-CSF or both to cultures from the six patients had no effect on CFU-E-derived colonies. In contrast, IL-3 but not GM-CSF induced a marked increase in the number (183%) and size of the BFU-E- derived colonies in five of the six cases and partially corrected the impaired dose-response to erythropoietin in four. Bone marrow from the other two patients yielded numbers of CFU-E and BFU-E colonies comparable to controls and manifested similar increments in colonies with increasing concentrations of erythropoietin. When IL-3 was added to these cultures, further increments were observed in the number and size of BFU-E colonies. We conclude that IL-3 enhanced the marrow erythropoiesis in most of the patients and exerted a corrective effect on the aberrant colony formation in the presence of erythropoietin. The data raise the possibility of IL-3 as a therapeutic agent in Diamond- Blackfan anemia.

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