The colony-stimulating factors (CSFs) promote the proliferation and differentiation of hematopoietic precursors and more recently have been shown to amplify the functions of mature phagocytes in vitro. In this study recombinant human granulocyte/macrophage colony-stimulating factor (rGM-CSF) was administered to cancer patients to determine whether the cytotoxic and secretory activity of their blood monocytes could be enhanced. Patients with refractory neoplastic disease were treated with rGM-CSF either as a single bolus or as a constant infusion for 14 days at either 100 or 500 micrograms/m2 per day. As has been reported by others, the number of peripheral blood monocytes and granulocytes rose markedly in a dose-response fashion during infusion with rGM-CSF. The functional capacity of monocytes was increased by rGM- CSF, since the cytotoxicity of monocytes against antibody-coated xenogeneic cells was increased during the constant infusion compared to baseline. In addition, monocytes harvested during the constant infusion and stimulated with lipopolysaccharide (LPS) in vitro secreted increased quantities of tumor necrosis factor alpha (TNF-alpha) and interferon (IFN). These data indicate that rGM-CSF can enhance both the number and the function of peripheral blood monocytes in vivo.
Macrophage-colony stimulating factor (M-CSF) has well-known effects on murine bone marrow, but its colony stimulating activity for human bone marrow is controversial. After treatment of human bone marrow with L- phenylalanine methylester (PME), macrophage-colonies (CFU-M) were induced by M-CSF in a dose-dependent fashion. The optimal concentration of recombinant human-macrophage colony stimulating factor (rhM-CSF) was 1,000 U/mL. Purified human urine M-CSF had colony stimulating activity similar to rhM-CSF. Further studies were performed to determine the factors responsible for the enhanced CFU-M formation from PME treated marrow. Compared with nylon wool and carbonyl iron monocyte depletion methods, PME eliminated significantly more monocytes and myeloid cells. This observation suggested that these cells may release hematopoietic inhibitory factors for CFU-M. Low concentrations (1%) but not normal (10%) concentrations of blood monocytes were inhibitory (mean inhibition, 48%) to CFU-M. High concentrations of monocytes (50%) augmented CFU-M colonies. HL-60 conditioned media was used to simulate secretory products of early myeloid cells. HL-60 conditioned media (1%) inhibited CFU-M formation but not granulocyte macrophage or granulocyte colonies. We conclude that M-CSF has colony stimulating activity for human marrow that can be recognized after removal of inhibitory cells by PME treatment.
Ten patients, with bone marrow failure or malignant disorders, became refractory to platelet transfusions using random, as well as partial or fully HLA-matched, single-donor platelets. To determine its effect on platelet refractoriness, intravenous gamma globulin (IV IgG) was administered at 400 or 800 mg/kg/d for five days, and postinfusion platelet responses were monitored. Platelet transfusion responses following intravenous gamma globulin (IV IgG) were graded as follows: Excellent, 48-hour posttransfusion count greater than 50,000/microL; good, 48-hour count greater than 20,000 but less than 50,000/microL; Fair, increased increment, 48-hour count less than 20,000; and failed, no increased increment. Six of ten patients (60%) had improved responses to selected single-donor platelets (two were excellent, three were good, and one was fair). The time to achieve a platelet transfusion count greater than 25,000/microL ranged from one to nine days of IgG therapy. One individual had sustained benefit (greater than 1 year); the remaining responses persisted for 6 to 8 weeks. These results suggest that IV IgG may be useful in the management of platelet refractoriness, especially in patients receiving single-donor platelets.
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