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E Vellenga

Publications and source records attributed to E Vellenga.

At least 19 recordsLinked to original sources
PubMed1995

Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients.

Initial studies have shown that recombinant human interleukin-6 (rhIL-6) induces anemia. Until now, the pathophysiologic mechanism of this induced anemia has been unknown. To unravel the underlying mechanism, we examined 15 cancer patients receiving rhIL-6 as an antitumor immunotherapy in a phase II study. rhIL-6 was administered subcutaneously at 150 micrograms once daily for 6 consecutive weeks. Various hematologic and biochemical parameters were measured weekly during rhIL-6 treatment and 4 weeks after rhIL-6 discontinuation. To determine plasma volume and red blood cell (RBC) volume, radioisotope dilution assays with labeled autologous RBCs and with human serum albumin were performed before rhIL-6 administration and on day 8 of rhIL-6 therapy. Hemoglobin levels decreased (mean change +/- SE) 7% +/- 1.5% within 3 days after the start of rhIL-6 therapy (P < .0001) and 19% +/- 2% at week 4. Levels had normalized at follow-up. The plasma volume increased 18% +/- 5% during the first week of rhIL-6 administration (P < .003), whereas RBC volume remained unaffected. The mean RBC corpuscular volume remained unchanged for 2 weeks and then began to decrease slowly, reaching its nadir at week 6 (5% +/- 1%; P < .01). Serum iron levels decreased 65% +/- 12% at week 4 (P < .002) and then returned to initial baseline values. Erythropoietin levels increased rapidly up to 68% at week 3 (P < .0001) and had normalized 4 weeks after rhIL-6 therapy. Levels of serum albumin, prealbumin, and transferrin decreased (P < .0001, P < .003, and P < .0001, respectively), whereas levels of serum amyloid A (P < .003), C-reactive protein, haptoglobin, and alpha-1-antitrypsin (P < .0001) increased during rhIL-6 treatment. All levels returned to pretreatment values after discontinuation of rhIL-6. No alterations in reticulocyte counts, serum lactic dehydrogenase levels, and bilirubin levels were observed. A 6-week regimen of subcutaneous rhIL-6 results in a rapid dilution anemia, caused by an acute and significant increase in plasma volume and followed by hypoferremia. This anemia is reversible after the cessation of rhIL-6 treatment.

Acute-Phase Proteins↗
PubMed1994

Mast cell growth factor modulates CD36 antigen expression on erythroid progenitors from human bone marrow and peripheral blood associated with ongoing differentiation.

To study the differentiation process of erythroid progenitors from normal human bone marrow and peripheral blood, CD34/CD36 sorted cells were cultured in the presence of Erythropoietin (Epo) and Epo plus mast cell growth factor (MGF). The CD34+/CD36- cell fraction from bone marrow supported 74 +/- 33 erythroid burst forming units (BFU-E)/10(4) cells (mean +/- SD, n = 4) in the presence of Epo, which increased 2.1-fold by coculturing with MGF. However, erythroid colony-forming units (CFU-E) were not cultured from the CD34+/CD36- cell fraction. In contrast, the CD34-/CD36+ cell fraction supported CFU-Es in the presence of Epo (152 +/- 115/10(5)) or Epo plus MGF (180 +/- 112/10(5)), whereas BFU-Es were hardly noticed. However, the transition of the BFu-E to CFU-E was observed by incubating CD34+/CD36- cells (10(4)/100 microL) in suspension with Epo plus MGF for 7 days followed by Epo in the colony assay. This was reflected by the appearance of CD34-/CD36+/Glycophorin A+/CD14- cells. In addition high numbers of CFU-Es (1,000 +/- 150, n = 4) were cultured from this cell fraction. In contrast to bone marrow erythroid progenitors, no peripheral blood CFU-Es were cultured from either the CD36+ or CD36- fraction, whereas BFU-Es were predominantly present in the CD36+ fraction. However, the CD34+ progenitor cell from peripheral blood did have intrinsic capacity to differentiate to CFU-Es because CD34+/CD36- cells incubated with Epo plus MGF for 7 days and followed by Epo in the colony assay, supported high numbers of CFU-Es (1,200 +/- 400, n = 3). To study whether additional growth factors have similar effects on erythroid progenitors, experiments were performed with interleukin 1 (IL-1), IL-3, and IL-6. IL-1 and IL-6 did not modulate the Epo supported proliferation and differentiation. In contrast, IL-3 in the presence of Epo did support CFU-Es, from CD34+/CD36- cells after 7 days in suspension culture. However, flow cytometry analysis showed that Epo plus IL-3 not only supported CD34-/CD36+/Glycophorin A+ cells but also CD36+/CD14+ cells, indicating the differentiation along different cell lineages. In summary, the data show a phenotypic distinction between bone marrow and peripheral blood erythroid progenitors with regard to CD36 expression. In addition, the results suggest that Epo plus MGF or IL-3 and preincubation in suspension culture are prerequisites for the transition of the BFU-E to the CFU-E.

Antigens, CD↗
PubMed1994

G(AnH)MTetra, a naturally occurring 1,6-anhydro muramyl dipeptide, induces granulocyte colony-stimulating factor expression in human monocytes: a molecular analysis.

N-Acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D-isoglutam yl-m- diaminopimelyl-D-alanine [G (Anh)MTetra], a naturally occurring breakdown product of peptidoglycan from bacterial cell walls, was studied for its ability to induce granulocyte colony-stimulating factor (G-CSF) mRNA and protein expression in human adherent monocytes. Resting monocytes did not express G-CSF mRNA or secrete G-CSF protein. In contrast, monocytes exposed to G(Anh)MTetra showed a dose-dependent increase in G-CSF mRNA accumulation, which correlates with the secretion of G-CSF protein. Maximal levels of G-CSF mRNA were reached within 2 h of activation. Expression of G-CSF was mediated by an increase in the stability of G-CSF transcripts rather than by an increase in the transcription rate of the G-CSF gene. Experiments with the protein synthesis inhibitor cycloheximide revealed that G(Anh)MTetra-induced G-CSF mRNA expression was independent of new protein synthesis. Furthermore, it was shown that the effect of G(Anh)MTetra was regulated by a protein kinase C-dependent pathway, whereas protein kinase A and tyrosine kinases were not involved. Finally, it was shown that G(Anh)MTetra also induced G-CSF mRNA expression in human endothelial cells. The data indicate that, besides lipopolysaccharide, other naturally occurring bacterial cell wall components are able to induce G-CSF expression in different hematopoietic cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1994

The application of hematopoietic growth factors in drug-induced agranulocytosis: a review of 70 cases.

Since 1989, granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF, G-CSF) have been increasingly applied in the treatment of drug-induced agranulocytosis. In order to evaluate the effectiveness of GM-CSF and G-CSF in the treatment of drug-induced agranulocytosis, we have studied all reported cases (n = 70) treated with GM-CSF and G-CSF, including ten patients treated during the last 2 years in The Netherlands. The results demonstrate that patients with a severe granulocytopenia (< 0.1 x 10(9)/l) treated with hematopoietic growth factors had a significantly faster recovery of the peripheral blood granulocytes compared to previous published studies. At the same time, a significantly lower mortality rate was observed. In patients with a severe granulocytopenia treated with GM-CSF or G-CSF a mortality rate of 5% was noted. No difference in granulocyte recovery was observed in patients treated with GM-CSF or G-CSF. The results of this review indicate that G-CSF and GM-CSF enhance the recovery of the myeloid lineage, resulting in a faster normalization of the peripheral blood granulocyte count and a reduced incidence of fatal complications.

Agranulocytosis↗
PubMed1993

[Hematopoietic growth factors as supportive treatment in drug-induced agranulocytosis].

This article describes the use of granulocyte macrophage colony stimulating factor and granulocyte colony stimulating factor in two patients with drug induced granulocytopenia. A granulocyte count > 1 x 10(9)/l was obtained after 7 days' treatment. These results suggest that the haematopoietic growth factors shortened the period of agranulocytosis and subsequently may improve the survival of these patients.

Aged↗
PubMed1993

Interferon-gamma enhances the LPS-induced G-CSF gene expression in human adherent monocytes, which is regulated at transcriptional and posttranscriptional levels.

Human adherent monocytes were studied with regard to the expression of granulocyte colony-stimulating factor (G-CSF) at mRNA and protein levels in response to lipopolysaccharide (LPS) and gamma-interferon (IFN-gamma) stimulation. Monocytes did not express G-CSF transcripts in response to IFN-gamma treatment. In contrast, monocytes exposed to IFN-gamma plus LPS showed a dose-dependent increase in G-CSF mRNA accumulation and protein secretion compared to LPS-stimulated monocytes. The augmented G-CSF mRNA expression in response to IFN-gamma plus LPS was the result of a slight increase in the G-CSF transcription rate (2.2-fold) and a more than 6-fold increase in the G-CSF mRNA half-life (20 minutes vs. > 120 minutes). In addition, it was shown that the effects of IFN-gamma on LPS-induced G-CSF protein secretion could be mimicked by the calcium ionophore A23187, suggesting that the Ca(2+)-dependent pathway might be triggered after binding of the ligand to the receptor. Finally, it was observed that the potentiating effects of IFN-gamma on LPS-induced G-CSF secretion could be blocked by interleukin-4 (IL-4). These data indicate that two cytokines produced by activated T cells have opposite effects on G-CSF production by human activated monocytes.

Blotting, Northern↗
PubMed1993

Recombinant human mast cell growth factor supports erythroid colony formation in polycythemia vera in the presence and absence of erythropoietin and serum.

The effect of mast cell growth factor (MGF) was studied on erythropoietin (Epo)-dependent and Epo-independent ("spontaneous") erythroid colony formation in patients with polycythemia vera (PV). MGF stimulated both Epo-dependent and Epo-independent erythroid colony formation from PV peripheral blood progenitor cells in vitro at a dose similar to normal erythroid progenitor. In addition, evidence was obtained that the stimulating effect of MGF was a direct effect on the erythroid progenitor and independent of serum. Antibodies against interleukin-1 (IL-1), IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and Epo could not abolish the enhancing effect of MGF. This was also supported by the finding that sorted CD34+ cells could be stimulated by MGF in the presence and absence of Epo. Finally, it was demonstrated that the spontaneous erythroid colony formation could not be ascribed to spontaneous release of MGF in the culture medium since anti-MGF did not affect the colony numbers. In conclusion, MGF has a direct stimulatory effect, independent of serum, on both Epo-dependent and Epo-independent erythroid colony formation in PV.

Antibodies↗
PubMed1992

Interleukin-4 (IL-4) receptor expression on human T cells is affected by different intracellular signaling pathways and by IL-4 at transcriptional and posttranscriptional level.

Interleukin-4 (IL-4) modulates the survival, proliferation, and differentiation of a variety of hematopoietic cells. The effects are mediated through a single class of high-affinity receptors for IL-4. To understand the biologic effects of IL-4 on human T cells, we studied the regulation of IL-4 receptor (IL-4R) gene expression. We showed that IL-4R mRNA accumulation in human T cells is enhanced fourfold after activation of different secondary signaling pathways by concanavalin A (Con A), phorbol myristate acetate (PMA), the calcium ionophore A23187, and combinations of these factors. This could be ascribed to an increase in the IL-4R transcription rate and to stabilization of IL-4R mRNA resulting in a half-life of 80 to 90 minutes (v 35 to 40 minutes in resting T cells). IL-4 did enhance the IL-4R mRNA accumulation by a factor 10, which was caused by an increase in the IL-4R transcription rate and prolonging the half-life of IL-4R transcripts to 140 to 160 minutes. Finally, it was shown that A23187 induced IL-4R mRNA expression is a protein synthesis-dependent process. In contrast, Con A-, PMA-, Con A + PMA-, and Con A + A23187-induced expression of IL-4R mRNA is protein-synthesis independent. Cyclosporine A inhibited the A23187- and Con A + A23187-induced IL-4R mRNA accumulation, whereas Con A-, PMA-, and Con A + PMA-induced IL-4R mRNA expression was not affected by this drug. These data indicate that expression of IL-4 receptors on human T cells can be modulated by different intracellular signaling pathways at both transcriptional and posttranscriptional levels.

Calcimycin↗
PubMed1992

The supportive effects of IL-7 on eosinophil progenitors from human bone marrow cells can be blocked by anti-IL-5.

Human rIL-7 was studied for its effects on myeloid and erythroid progenitors from human bone marrow cells. IL-7 did not support the granulocytic/monocytic or erythroid lineage but exclusively stimulated eosinophil colony formation (CFU-Eo) (4 +/- 3 vs 48 +/- 17 CFU-Eo/10(5) nonadherent fraction-non-T cell (NAF-NT) cells). This supportive effect was not mediated by T cells or monocytes because similar results were obtained with or without T cell or adherent depleted cell fractions. In addition, it was shown that CD34+ sorted cells could be stimulated by IL-7 (0 vs 15 +/- 9 CFU-Eo/3 x 10(3) CD34+ cells) Furthermore studies with IL-3 or granulocyte-macrophage CSF (GM-CSF) demonstrated an additive effect on the IL-7 supported colony formation. Finally, experiments were performed with anti-IL-3, anti-GM-CSF, anti-IL-1, and anti-IL-5 to exclude the possibility that IL-7 indirectly stimulated the eosinophil progenitor cell. Anti-GM-CSF, anti-IL-1, or anti-IL-3 did not influence the supportive effects of IL-7. However, anti-IL-5 did abolish the effects of IL-7 on the eosinophil colony formation (69 +/- 15 vs 3 +/- 2 CFU-Eo/10(5) NAF-NT, n = 3). Similar results were obtained with CD34+ sorted cells. Moreover, IL-5 mRNA expression could be demonstrated in IL-7-stimulated NAF-NT cells. These data suggest that the supportive effects of IL-7 on eosinophil precursors are mediated by the endogenous release of IL-5.

Antigens, CD↗
PubMed1992

Effects of interleukin-3 after chemotherapy for advanced ovarian cancer.

To define the maximum tolerated dose and to study whether recombinant human interleukin-3 (rhIL-3) reduced chemotherapy-induced neutropenia and thrombocytopenia, 20 chemotherapy-naive patients with advanced ovarian cancer eligible for treatment with 6 cycles of carboplatin-cyclophosphamide every 4 weeks (day 1) were entered in a phase I/II open, single-center trial. Cohorts of five patients received during 7 days 1, 5, 10, or 15 micrograms/kg/d rhIL-3 (days 5 through 11) in cycles 1, 3, and 5 by continuous intravenous (IV) infusion or once daily subcutaneous (SC) administration. In control cycles 2, 4, and 6, no rhIL-3 was administered. rhIL-3 significantly increased the recovery of leukocyte, neutrophil, and platelet counts, especially at 5, 10, and 15 micrograms/kg rhIL-3. rhIL-3 also increased basophil, eosinophil, monocyte, and lymphocyte counts at this dose steps. Effects on reticulocytes were limited. No difference in efficacy between SC and IV rhIL-3 treatment was found. Chemotherapy postponement for insufficient bone marrow recovery was necessary in 22 of 45 control cycles versus 2 of 49 rhIL-3 cycles (P less than .001). Platelet transfusions were required in 7 of 45 control cycles versus 3 of 50 rhIL-3 cycles (P less than .5). rhIL-3 up to 10 micrograms/kg/d could be administered without severe side effects. At 15 micrograms/kg/d, rhIL-3 headache was dose-limiting. Other side effects were fever, flu-like symptoms, nausea, skin rash, flushing, facial erythema, and urticaria. Liver toxicity occurred in rhIL-3 and control cycles. rhIL-3 slightly increased tumor necrosis factor alpha, C-reactive protein, and serum amyloid A plasma levels, whereas no effect on IL-6 plasma levels was observed. rhIL-3 administered SC appears to be an interesting hematopoietic growth factor for reduction of chemotherapy-induced myelotoxicity.

Adolescent↗
PubMed1992

Correction of neutropenia by GM-CSF in patients with a large granular lymphocyte proliferation.

The in vivo and in vitro effects of GM-CSF were tested in four patients with large granular lymphocyte proliferation (LGLP) and severe granulocytopenia. All patients had an increased percentage of LGL cells (greater than 20%), whereas 3/4 patients demonstrated rearranged T-cell-receptor genes. An effect on the peripheral granulocyte counts was noticed in 3/4 patients after 14 days of GM-CSF administration (5 micrograms/kg/day, subcutaneously); 2.5, 7, and 0.45 x 10(9)/l, respectively. These changes were associated with a two- to five-fold increase in monocytes and a strong increment in eosinophils. In one patient GM-CSF was not effective in increasing the granulocyte count. B lymphocytes showed a variable increase, ranging from 1.2-fold to 3.8-fold, while the number of NK cells remained almost constant during the GM-CSF treatment. No consistent effect of GM-CSF on T lymphocytes was observed. These data suggest that GM-CSF may be a therapeutic option in some patients with LGLP complicated by granulocytopenia and/or infection.

Adult↗
PubMed1992

Effects of recombinant human interleukin-3 in patients with relapsed small-cell lung cancer treated with chemotherapy: a dose-finding study.

PURPOSE: The aim of the study was to determine the maximum tolerable dose of recombinant human interleukin-3 (rhIL-3) after combination chemotherapy and to evaluate the ability of rhIL-3 to influence hematopoietic recovery. PATIENTS AND METHODS: Nineteen patients who had relapsed small-cell lung cancer (SCLC) received rhIL-3 after their second course of chemotherapy, which consisted of either cyclophosphamide, doxorubicin, and etoposide (CDE) every 3 weeks or vincristine, ifosfamide, mesna, and carboplatin (VIMP) every 4 weeks. Twenty-four hours after the last chemotherapy dose, rhIL-3 was administered subcutaneously (SC) once daily for 14 days on an outpatient basis. Escalating dosages (1, 2, 4, 8, and 16 micrograms/kg/d) of rhIL-3 were tested. Hematologic effects were evaluated by comparing blood cell recovery after chemotherapy cycle 1 and cycle 2 plus rhIL-3. RESULTS: The adverse effects of rhIL-3 at dosages up to 8 micrograms/kg/d consisted mainly of low-grade fever and flulike symptoms. At 16 micrograms/kg, rhIL-3 headache became dose-limiting. Severe neutropenia (neutrophils less than 0.5 x 10(9)/L) after VIMP cycle 2 was shorter in duration than after cycle 1 (7 v 3 days; P less than .05). At rhIL-3 dose levels 8 and 16 micrograms/kg, hematologic effects in seven patients who were treated with VIMP showed a significant hastened recovery of leukocyte and neutrophil counts during cycle 2 compared with cycle 1 and increased monocyte and eosinophil counts in cycle 2 compared with cycle 1. rhIL-3 also increased reticulocyte and platelet counts at a dose level of 8 micrograms/kg. No significant stimulation of basophils and lymphocytes was observed. Apart from the hematologic effects, rhIL-3 also augmented the release of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and lowered cholesterol levels. CONCLUSIONS: This study demonstrates that rhIL-3 can be safely administered after chemotherapy on an outpatient basis. rhIL-3 is tolerated well at doses up to 8 micrograms/kg/d and is biologically active in patients after myelosuppressive chemotherapy.

Adult↗
PubMed1992

Sulfasalazine induced agranulocytosis treated with granulocyte-macrophage colony stimulating factor.

We report the use of granulocyte-macrophage colony stimulating factor (GM-CSF) in a case of rheumatoid arthritis with sulfasalazine induced agranulocytosis, leading to a rapid bone marrow recovery within 7 days. This case and 2 others reported in the literature emphasize the need for further research into the possible role of GM-CSF in the treatment of drug induced agranulocytosis.

Adult↗
PubMed1992

The effects of IL-1 beta and IL-4 on the proliferation and endogenous secretion of growth factors by acute myeloblastic leukemic cells.

The effects of interleukin-1 beta (IL-1) and IL-4 were studied on the proliferation of acute myeloid leukemia (AML) cells. IL-1 stimulated tritiated thymidine (3H-TdR) uptake of AML cells in 8/12 cases, whereas IL-4 enhanced 3H-TdR uptake in 5/12. Combination of both factors resulted in an additive effect in 6/12 cases which could be abrogated by the addition of anti-granulocyte-macrophage colony stimulating factor (GM-CSF). To study whether IL-1, IL-4, or IL-1 plus IL-4 affects the AML progenitor cell directly or indirectly by the release of endogenous factors, supernatants of stimulated AML cells (n = 6) were analyzed for GM-CSF, IL-6, and tumor necrosis factor-alpha (TNF) production. IL-1 induced the endogenous secretion of GM-CSF, IL-6, and TNF in most cases. In contrast, no secretion of growth factors was induced by IL-4, whereas in 2 cases IL-4 suppressed the IL-1-induced secretion of GM-CSF, TNF, and IL-6. This was associated with a decline in the proliferative response to IL-1 measured in a clonogenic assay. In addition it was shown that exogenous supplied GM-CSF and TNF could raise the suppressive effects of IL-4 on the IL-1-supported proliferation. In summary these data indicate that the IL-4-supported proliferation is not caused by the endogenous secretion of GM-CSF, IL-6, and TNF. Furthermore the suppressive effect of IL-4 on the IL-1-induced proliferation in some cases may be caused by a reduced secretion of GM-CSF, TNF, and IL-6.

Cell Division↗