Human recombinant granulocyte-macrophage colony stimulating factor and interleukin 3 have overlapping but distinct hematopoietic activities.

Emerson, SG; Yang, Yu Chung; Clark, Steven C.; Long, Michael W.

doi:10.1172/jci113727

Cited by 129 publications

(29 citation statements)

References 20 publications

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“…IL-3 and GM-CSF stimulate the growth of overlapping but less mature CFU-GM, while G-CSF stimulates more differentiated myeloid progenitors. 38,39 The ATRA enhancing activity on CFU-GM grown with IL-3 and GM-CSF and lack of effect with G-CSF, probably implies that the target cells for ATRA growth stimulation are less mature IL-3 and GM-CSF-responding myeloid progenitors but not the more mature G-CSF-responding progenitor cells. Our time-delayed experiments support this possibility by showing that the enhancing activity of ATRA was maximal when the compound was added early in the course of the culture, while the colonies were still at their early stages of maturation.…”

Section: Discussionmentioning

confidence: 99%

All-trans-retinoic acid effects the growth, differentiation and apoptosis of normal human myeloid progenitors derived from purified CD34+ bone marrow cells

et al. 2000

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We have previously shown that all-trans retinoic acid (ATRA) increases the number of CFU-GM colonies grown from unseparated human bone marrow cells with crude sources of colony stimulating factors. In this study, we further characterized the effect of ATRA on the growth of CFU-GM stimulated by individual cytokines from multiple samples of CD34 ؉ enriched or purified human bone marrow cells. The number of IL-3-or GM-CSF-induced CFU-GM with 3 ؋ 10 ؊7 M ATRA was 3.25 ± 1.13, and 2.17 ؎ 0.8-fold greater respectively, compared to controls without ATRA, while G-CSF had no effect and the ratio of colony-induced with or without ATRA was 1.06 ؎ 0.17 (P ‫؍‬ 0.00012). No colonies grew with ATRA ؉ IL-6 or ATRA without a cytokine. Maximum enhancing effect on IL-3-induced CFU-GM occurred when ATRA was added on day 2, gradually diminished when delaying ATRA, and in cultures of day 9 or older adding ATRA had no effect. In 14 days liquid cultures of purified CD34 ؉ cells with IL-3, ATRA increased the number of myeloid differentiated cells to 91-95%, compared to 37-70% with IL-3 alone. In addition, the number of apoptotic cells using the annexin V method increased after 14 days from 5.1% with IL-3 to 17.1% with IL-3 ؉ ATRA and by the TUNEL in situ method from 10-26% to 60-95%, respectively. This study demonstrates that ATRA consistently enhances the growth of myeloid progenitors from CD34 ؉ cells. This effect is dependent on the stimulating cytokine, suggesting the myeloid cells responding to ATRA are the less mature CFU-GMs that are targets of IL-3 and GM-CSF and not the G-CSF-responding mature progenitors. The growth stimulation by ATRA and IL-3 is also associated with granulocyte differentiation and increased apoptosis. These studies further suggest a potential role of pharmacological doses of ATRA on the development of normal human hematopoietic cells. Leukemia (2000) 14, 874-881.

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Section: Discussionmentioning

confidence: 99%

All-trans-retinoic acid effects the growth, differentiation and apoptosis of normal human myeloid progenitors derived from purified CD34+ bone marrow cells

et al. 2000

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“…Human GM-CSF and IL-3 has been shown to promote formation of CFU-GM when added to the BM cell cultures (14), whereas human M-CSF and IL-34 promoted CFU-M formation (13). Recent development of humanized mice has opened up the possibility to study human monocyte and macrophage development in vivo and the role of cytokines in this process.…”

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confidence: 99%

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Chen

Zheng

et al. 2013

The Journal of Immunology

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Engraftment of human CD34+ hematopoietic stem/progenitor cells into immunodeficient mice leads to robust reconstitution of human T and B cells but not monocytes and macrophages. To identify the cause underlying the poor monocyte and macrophage reconstitution, we analyzed human myeloid cell development in humanized mice and found that it was blocked at the promonocyte stage in the bone marrow. Expression of human M-CSF or GM-CSF by hydrodynamic injection of cytokine-encoding plasmid completely abolished the accumulation of promonocytes in the bone marrow. M-CSF promoted the development of mature monocytes and tissue-resident macrophages whereas GM-CSF did not. Moreover, correlating with an increased human macrophages at the sites of infection, M-CSF–treated humanized mice exhibited an enhanced protection against influenza virus and Mycobacterium infection. Our study identifies the precise stage at which human monocyte/macrophage development is blocked in humanized mice and reveals overlapping and distinct functions of M-CSF and GM-CSF in human monocyte and macrophage development. The improved reconstitution and functionality of monocytes/macrophages in the humanized mice following M-CSF expression provide a superior in vivo system to investigate the role of macrophages in physiological and pathological processes.

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“…28,46 This molecule has been used as a single agent in patients with bone marrow failure; and increases in granulocytes, monocytes, and eosinophils have been demonstrated. 23,47 Both platelet increases and platelet decreases occur, albeit infrequently.…”

Section: Discussionmentioning

confidence: 99%

“…48 IL-3 and GM-CSF have overlapping but distinct activities. 46 In addition, in vitro data demonstrate that a combination of IL-3 and GM-CSF is more potent than either used alone. 32,49,50 Sequential administration of IL-3 followed by GM-CSF resulted in a shortened duration of neutropenia and attenuation of thrombocytopenia and anemia in patients who were treated with high-dose chemotherapy for lymphoma or breast carcinoma with or without autologous BMT.…”

Section: Discussionmentioning

confidence: 99%

Sequential interleukin 3 and granulocyte‐macrophage–colony stimulating factor therapy in patients with bone marrow failure with long‐term follow‐up of responses

Talpaz

Champlin

et al. 2003

Cancer

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BACKGROUNDInterleukin‐3 (IL‐3) and granulocyte‐macrophage–colony stimulating factor (GM‐CSF) have synergistic, hematopoietic growth‐promoting activity in preclinical studies. Because of the paucity of effective therapies for patients with chronic bone marrow failure states, the authors studied the biologic activity of sequential IL‐3/GM‐CSF in such patients.METHODSIL‐3 was given subcutaneously for 5 days (at escalating doses of 0.15 μg/kg, 0.3 μg/kg, 0.6 μg/kg, 1.2 μg/kg, 2.5 μg/kg, 5.0 μg/kg, 10.0 μg/kg, or 15.0 μg/kg per day), and GM‐CSF for was given subcutaneously for 9 days (at a dose of 5 μg/kg per day; Phase I 3 + 3 design) followed by 14 days of rest (total, 2 courses), then maintenance therapy.RESULTSThe majority of 38 evaluable patients had aplastic anemia or myelodysplastic syndrome. Most patients (79%) had neutrophil responses. Ten patients (26%), all of whom were treated with IL‐3 doses ≥ 1.2 μg/kg per day, had platelet responses, with a median increase of 132 × 109/L (range, 41–180 × 109/L) over baseline in responders. Six patients (16%) had trilineage recovery, which could be durable (the longest ongoing at 6.5 years after therapy completion). The most common toxicities were low‐grade fever, headache, and fatigue. The maximum tolerated doses were IL‐3 at 10 μg/kg per day and GM‐CSF at 5 μg/kg per day.CONCLUSIONSSequential IL‐3/GM‐CSF effectively raised blood counts in some patients with bone marrow failure at doses that were tolerated well. These results indicate that early‐acting growth factors can induce durable, multilineage responses in a subset of individuals with bone marrow failure. Cancer 2003. © 2003 American Cancer Society.

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Human recombinant granulocyte-macrophage colony stimulating factor and interleukin 3 have overlapping but distinct hematopoietic activities.

Cited by 129 publications

References 20 publications

All-trans-retinoic acid effects the growth, differentiation and apoptosis of normal human myeloid progenitors derived from purified CD34+ bone marrow cells

All-trans-retinoic acid effects the growth, differentiation and apoptosis of normal human myeloid progenitors derived from purified CD34+ bone marrow cells

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Sequential interleukin 3 and granulocyte‐macrophage–colony stimulating factor therapy in patients with bone marrow failure with long‐term follow‐up of responses

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