Combination protocols of cytokine therapy with interleukin-3 and granulocyte-macrophage colony-stimulating factor in a primate model of radiation-induced marrow aplasia

Experimental Hematology Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603.
Blood (Impact Factor: 10.45). 12/1993; 82(10):3012-8.
Source: PubMed


Single cytokine therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) has been shown to be effective in decreasing the respective periods of neutropenia and thrombocytopenia following radiation- or drug-induced marrow aplasia. The combined administration of IL-3 and GM-CSF in normal primates suggested that a sequential protocol of IL-3 followed by GM-CSF would be more effective than that of GM-CSF alone in producing neutrophils (PMN). We investigated the therapeutic efficacy of two combination protocols, the sequential and coadministration of recombinant human IL-3 and GM-CSF relative to respective single cytokine therapy, and delayed GM-CSF administration in sublethally irradiated rhesus monkeys. Monkeys irradiated with 450 cGy (mixed fission neutron:gamma radiation) received either IL-3, GM-CSF, human serum albumin (HSA), or IL-3 coadministered with GM-CSF for days 1 through 21 consecutively postexposure, or IL-3 or HSA for days 1 through 7 followed by GM-CSF for days 7 through 21. All cytokines and HSA were injected subcutaneously at a total dose of 25 micrograms/kg/d, divided twice daily. Complete blood counts (CBC) and platelet (PLT) counts were monitored over 60 days postirradiation. The respiratory burst activity of the PMN was assessed flow cytometrically, by measuring hydrogen peroxide (H2O2) production. Coadministration of IL-3 and GM-CSF reduced the average 16-day period of neutropenia and antibiotic support in the control animals to 6 days (P = .006). Similarly, the average 10-day period of severe thrombocytopenia, which necessitated PLT transfusion in the control animals, was reduced to 3 days when IL-3 and GM-CSF were coadministered (P = .004). The sequential administration of IL-3 followed by GM-CSF had no greater effect on PMN production than GM-CSF alone and was less effective than IL-3 alone in reducing thrombocytopenia. PMN function was enhanced in all cytokine-treated animals.

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Available from: Thomas J Macvittie, Dec 11, 2014
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    • "There are several similar reports demonstrating the additive and synergistic effects of G-CSF in combination with synthokine SC-55494 (synthetic IL-3 receptor agonist), glucan (macrophage activator), mast cell growth factor (c-kit ligand), and IL-6 in mouse and NHP models for survival or improvement of myelosuppression (neutropenia/thrombocytopenia) [50] [51] [52] [53] [54] [55]. There is an additional report demonstrating the beneficial effects of combining IL-3 and GM-CSF in NHP exposed to 4.5 Gy of mixed fission neutron: c-radiation [56]. The combined treatment consisted of IL-3 and GM-CSF each administered (sc), two times a day, with doses of 12.5 lg/kg. "
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    ABSTRACT: One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. As such, this type of security threat is considered to be of relatively low risk, but one that would have an extraordinary high impact on health and well-being of the US citizenry. Psychological counseling and medical assessments would be necessary for all those significantly impacted by the nuclear/radiological event. Direct medical interventions would be necessary for all those individuals who had received substantial radiation exposures (e.g., >1Gy). Although no drugs or products have yet been specifically approved by the United States Food and Drug Administration (US FDA) to treat the effects of acute radiation syndrome (ARS), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and pegylated G-CSF have been used off label for treating radiation accident victims. Recent threats of terrorist attacks using nuclear or radiologic devices makes it imperative that the medical community have up-to-date information and a clear understanding of treatment protocols using therapeutically effective recombinant growth factors and cytokines such as G-CSF and GM-CSF for patients exposed to injurious doses of ionizing radiation. Based on limited human studies with underlying biology, we see that the recombinants, G-CSF and GM-CSF appear to have modest, but significant medicinal value in treating radiation accident victims. In the near future, the US FDA may approve G-CSF and GM-CSF as 'Emergency Use Authorization' (EUA) for managing radiation-induced aplasia, an ARS-related pathology. In this article, we review the status of growth factors for the treatment of radiological/nuclear accident victims.
    Cytokine 09/2014; 71(1):22-37. DOI:10.1016/j.cyto.2014.08.003 · 2.66 Impact Factor
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    • "Previous studies had demonstrated that IL-1β is an important cytokine for radioprotection (Neta et al., 1994; Neta et al., 1986). IL-3 can regulate the radiation-induced the myelo-suppression by producing the platelets and neutrophils (Farese et al., 1993). In this study, ZOE increased levels of IL-1β and IL- 3 in the sera after γ-rays irradiation (Figure 6), suggesting ZOE reduced the bone marrow cells injures induced by irradiation through enhancing secretion of cytokines for radio-protection. "
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    • "IL-1 derived nonapeptide Protects mice against irradiation effects, lacks toxic effects Boraschi et al., (1988); Frasca et al., (1991) Palmitoylated nonapeptide Protects mice against effects of irradiation better than IL-1 nonapeptide, inhibits LPS stimulated production of nitric oxide Bajpai et al., (1998); Singh et al., (2004) IL-3 Decreases periods of neutropenia and thrombocytopenia, more effectively when administered with GM-CSF Farese et al., (1993) Synthokine (IL-3R agonist) Reduces duration of thrombocytopenia, more effective in combination with GM-CSF Farese et al., (1996a); MacVittie et al., (1996) Daniplestim (IL-3R) In combination with Mpl-L improves hematopoietic recovery, reduces clinical support requirements in animals Farese et al., (1998) IL-6 Therapeutic administration accelerates multilineage hematopoietic recovery, enhances regeneration of platelets and enhances G-CSF mediated effects of recovery, more effective in combination with IL-3 MacVittie et al., (1994); Patchen et al., (1991, 1993a) "
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