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PubMed1995

Hematopoietic progenitor cell mobilization into the peripheral blood of mice using a combination of recombinant rat stem cell factor (rrSCF) and recombinant human granulocyte colony-stimulating factor (rhG-CSF).

A significant increase in the hematopoietic stem cell (HSC) concentration has been observed in the peripheral blood and spleen of mice treated with rhG-CSF alone or with a combination of rhG-CSF plus rrSCF. The longer the duration of cytokine treatment, the higher the stimulatory effect on stem cell mobilization. In addition, cytokine administration led to a reduced stem cell concentration in the bone marrow. The total amount of HSCs in the body did not change following cytokine administration. These data support the theory that stem cells are mobilized from the bone marrow into circulation, as opposed to expanding in blood and spleen. In sharp contrast to rhG-CSF alone, a combination of rhG-CSF plus rrSCF produced a strong increase in the self-maintenance ability of peripheral blood day 11 colony-forming units-spleen (CFU-S-11). After 10 days of cytokine treatment, long-term culture initiating cells (LTC-IC) were seen in the peripheral blood; in normal mice, the content of LTC-IC in the blood was below the detection level. The activation of stromal progenitors (cells capable of transferring the hematopoietic microenvironment) by cytokine treatment was observed here for the first time. The results suggest that a combination of rhG-CSF plus rrSCF is more effective than rhG-CSF alone in obtaining a large amount of transplantable HSCs.

Animals↗
PubMed1994

Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis, and clinical effects.

Macrophage colony-stimulating factor (M-CSF) is a known inducer of proliferation and differentiation of cells of the mononuclear phagocyte lineage, and gamma-interferon (gamma-IFN) is a known activator of mononuclear phagocytes. In this Phase I clinical trial of combined therapy with M-CSF and gamma-IFN, 36 patients were treated with 14-day continuous infusions of M-CSF at doses ranging from 10 to 140 micrograms/kg/day. In all but five patients, gamma-IFN was administered by daily s.c. injection on days 8-14 of the M-CSF infusion at doses of 0.05 or 0.1 mg/m2/day. A total of 73 courses of M-CSF and 66 courses of gamma-IFN were administered. The maximally tolerated dose combination was 120 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN. The addition of gamma-IFN did not alter the maximally tolerated dose of M-CSF therapy, although some additional toxicities were noted with combined therapy. At the 140-micrograms/kg/day M-CSF dose level, grade 4 thrombocytopenia occurred in 2 of 3 patients, with a median platelet count nadir of 26,000/mm3 after 7-10 days of M-CSF infusion. At this dose level, there was one reversible grade 3 hepatic toxicity, and one grade 3 exacerbation of underlying chronic obstructive lung disease. Peripheral blood monocytosis was observed at all M-CSF dose levels exceeding 40 micrograms/kg/day, approaching 3-fold elevations at the 100-micrograms/kg/day M-CSF dose level. The induction of monocytosis was correlated with the development of thrombocytopenia. At the conclusion of therapy with 100 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN, 78% of peripheral blood monocytes expressed the low affinity Fc gamma receptor for aggregated immunoglobulin, Fc gamma RIII (CD16), and CD14 was expressed by only 36% of the cells. This phenotype has been shown previously to be associated with cellular activation. In contrast, 35% of monocytes from patients treated with M-CSF therapy alone at the same dose expressed CD16 and 88% expressed CD14. A partial clinical response was noted in a patient with metastatic renal cell carcinoma, and minor clinical responses were observed in patients with a diffuse/follicular lymphoma, metastatic renal cell carcinoma, and metastatic thymoma. At M-CSF doses exceeding 20 micrograms/kg/day within the maximally tolerated dose range, gamma-IFN did not modulate the ability of M-CSF to reliably induce peripheral blood monocytosis. This study shows that M-CSF and gamma-IFN therapy induces the proliferation and differentiation of circulating mononuclear phagocytes.

Adult↗
PubMed1996

Recombinant human interleukin-3 (rhIL-3) enhances the mobilization of peripheral blood progenitor cells by recombinant human granulocyte colony-stimulating factor (rhG-CSF) in normal volunteers.

To identify a precisely timed and safe protocol for progenitor cell mobilization, we studied the effects of rhIL-3 and rhG-CSF administration to normal volunteers. rhG-CSF 5 micrograms/kg/d was administered subcutaneously (s.c.) for 7 consecutive days either alone or preceded by rhIL-3 5 micrograms/kg/d s.c. for 4 consecutive days in sequential or partially overlapping schedules. The combined cytokines were well-tolerated--adverse effects were similar to those of the individual agents. Total white blood cell (WBC) and neutrophil counts rose briskly in response to rhG-CSF, and peak mean values were similar between treatment cohorts. Mean platelet counts were modestly elevated during rhG-CSF treatment only in the cohorts receiving rhIL-3 and rhG-CSF. Mean circulating CD34+ cells peaked on day 5 in the rhG-CSF group (38.9+/-14.3/microliter), day 6 in the sequential rhIL-3/rhG-CSF group (56.4+/-12.4/microliter), and day 6 in the partial overlap group (46.1+/-10.9/microliter). On day 3, mean CD34+ cell counts of the subjects who received sequential treatment were markedly higher than observed in the other groups (p<0.05) and were estimated to have been sufficient for collection of adequate grafts by single 10-L leukapheresis procedures in 60% of subjects. Circulating clonogenic cells (CFU-GM and/or BFU-E) were substantially higher in the sequential group than the rhG-CSF group on days 3-6 but were only minimally elevated above baseline in the partial overlap group. The numbers of circulating CD34+/Lin-/Thy-1+ cells (putative stem cells) were increased substantially, especially in the sequential group. On the basis of this pilot trial, we conclude that priming with rhIL-3 is a safe and well-tolerated method for enhancing the mobilization of human blood progenitors and stem cells by rhG-CSF.

Adult↗