Human IL-3 and GM-CSF Act Synergistically in Stimulating Hematopoiesis in Primates

Donahue, Robert E.; Seehra, Jasbir; Metzger, Meredith B.; Lefebvre, Denise; Rock, Brian A.; Carbone, Suzanne; Nathan, David G.; Garnick, Marc B.; Sehgal, Prabhat K.; Laston, David; LaVallie, Edward R.; McCoy, J. Philip; Schendel, Paul F.; Norton, Christine R.; Turner, Katherine J.; Yang, Y C; Clark, Steven C.

doi:10.1126/science.3051378

Cited by 299 publications

(67 citation statements)

References 21 publications

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“…Preclinical studies of rhIL-3 in animal models showed a modest and delayed increase in neutrophils, basophils, and eosinophils. Increases in reticulocyte counts and variable increases in platelet counts were also observed (Metcalf et al, 1986;Donahue et al, 1988;Wagemaker et al, 1990).…”

mentioning

confidence: 89%

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Dercksen

Hoekman²,

Huinink³

et al. 1993

Br J Cancer

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Summary Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression.Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 fig/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed.Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x ), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhlL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin, etoposide and ifosfamide. Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 pg/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated.In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.

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confidence: 89%

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Dercksen

Hoekman²,

Huinink³

et al. 1993

Br J Cancer

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“…Either IL-3 or GM-CSF is required for survival of stem cells (Leary et al, 1992), and the two factors can act synergistically in stimulating haemopoiesis (Donahue et al, 1988). IL-6 is thought to function by shortening the dormancy period of stem cells and triggering cell division of dormant cells (Leary et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Long‐term stromal cultures produce dendritic‐like cells

O’Neill

1997

Br J Haematol

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Summary.A stromal cell-dependent long-term culture (LTC) system has been developed from spleen which continuously generates non-adherent cells with dendritic cell (DC) characteristics. Bioassays using factor-dependent cell lines have revealed that both spleen and thymic stromal cultures secrete interleukin (IL)-3 and IL-6-like growth factors. Conditioned medium from LTC also contains factors which appear to be unrelated to IL-3 and induces growth of stromal cells from bone marrow. Non-adherent cells generated in LTC were not T or B lymphoid cells or granulocytes, nor were mast cells detectable. Morphological and electron microscopic examination has also excluded the presence of macrophages (Mø). Cells with DC morphology have been detected by both light and electron microscopy. The majority of cells in the non-adherent population were found to have multiple membrane pseudopodia, with a small acentric nucleus. These appear to be the precursors of DC. They expressed cell surface markers detectable with DC-specific antibodies and antibody specific for major histocompatibility complex Class II molecules. A proportion of cells also expressed myeloid markers, but since this expression was not supported by histochemical staining for myeloperoxidase or non-specific esterase, it was concluded that the cells produced are not typical of the myeloid lineage. Cells generated in LTC were shown to be potent stimulators for allogeneic and syngeneic MLR and for antigen-specific T-cell proliferation.

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“…In addition, IL-3 has been used in culture to produce blood cells of various lineages, including neutrophils, monocytes, erythrocytes, megakaryocytes, basophils, eosinophils, mast cells, and B-lymphoid cells [2,5,[9][10][11][12][13]. Administration of IL-3 to human and primate subjects has enhanced multilineage-hematopoiesis [14][15][16][17]. Autologous progeny cells after culture/expansion in cytokine combination including IL-3 have been successfully infused into patients after a nonmyeloablative conditioning regimen [18].…”

Section: Introductionmentioning

confidence: 99%

Correlation Between IL‐3 Receptor Expression and Growth Potential of Human CD34 ⁺ Hematopoietic Cells from Different Tissues

Huang¹,

Chen²,

Yu³

et al. 1999

STEM CELLS

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CD123 (␣-subunit of IL-3 receptor) expression on primitive and committed human hematopoietic cells was studied by multicolor sorting and single-cell culture. The sources of cells included fetal liver (FLV), fetal bone marrow, umbilical cord blood, adult bone marrow and mobilized peripheral blood. Three subsets of CD34 + cells were defined by the levels of surface CD123: CD123 negative , CD123 low , and CD123 bright . Coexpression of lineage markers showed that a majority of CD34 + CD123 bright cells were myeloid and B-lymphoid progenitors, while erythroid progenitors were mainly in the CD34 + CD123 negative subset. The CD34 + CD123 low subset contained a heterogeneous distribution of early and committed progenitor cells. Single CD34 + cells from the CD123 subsets were cultured in a cytokine cocktail of stem cell factor, interleukin 3 (IL-3), IL-6, GM-CSF, erythropoietin, insulin-like growth factor-1, and basic fibroblast growth factor. After 14 days of incubation, a higher cloning efficiency (CE) was observed in the CD34 + CD123 negative and CD34 + CD123 low fractions (37 ± 23% and 44 ± 23%, respectively) than in the CD34 + CD123 bright fraction (15 ± 21%). Using previously published criteria that colonies containing dispersed, translucent cells (dispersed growth pattern, DGP) were derived from primitive cells and that colonies composed solely of clusters were from committed cells, early precursors were distributed evenly in the CD34 + CD123 negative and CD34 + CD123 low subsets. When CD38 and CD90 (Thy-1) were used for further characterization of CD34 + cells from FLV, CE increased from 37 ± 23% in CD123 negative to 70 ± 19% in CD123 negative CD38 -and from 44 ± 23% in CD123 low to 66 ± 19% in CD123 low CD38 -. No significant increase in CE or DGP progenitors was observed when CD34 + cells were sorted by CD90 and CD123. We concluded that: A) high levels of CD123 were expressed on B-lymphoid and myeloid progenitors; B) early erythroid progenitors had little or no surface CD123, and C) primitive hematopoietic cells are characterized by CD123 negative/low expression.

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Human IL-3 and GM-CSF Act Synergistically in Stimulating Hematopoiesis in Primates

Cited by 299 publications

References 21 publications

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Long‐term stromal cultures produce dendritic‐like cells

Correlation Between IL‐3 Receptor Expression and Growth Potential of Human CD34 ⁺ Hematopoietic Cells from Different Tissues

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Human IL-3 and GM-CSF Act Synergistically in Stimulating Hematopoiesis in Primates

Cited by 299 publications

References 21 publications

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Long‐term stromal cultures produce dendritic‐like cells

Correlation Between IL‐3 Receptor Expression and Growth Potential of Human CD34 + Hematopoietic Cells from Different Tissues

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Product

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Correlation Between IL‐3 Receptor Expression and Growth Potential of Human CD34 ⁺ Hematopoietic Cells from Different Tissues