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E Vellenga

Publications and source records attributed to E Vellenga.

At least 73 records · Page 4Linked to original sources
PubMed2000

Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl-lysophospholipid ET-18-OCH(3).

Hyperthermia has been shown to be a potential purging modality in autologous stem cell transplantation settings owing to its selective toxicity towards leukaemic cells. We describe two approaches to further increase the therapeutic index of the hyperthermic purging modality by using normal murine bone marrow cells and a murine model for acute myeloid leukaemia. First, the tetrapeptide AcSDKP was used to protect the normal haematopoietic progenitor cells against hyperthermic damage. Pretreatment for 8 h at 37 degrees C with 1 x 10(-9) mol/l AcSDKP resulted in a decrease in hyperthermic sensitivity of only normal haematopoietic progenitor cells. This combined treatment protocol revealed a therapeutic index (ratio of surviving fractions of normal vs. leukaemic cells) of > 500, which was considered to be sufficient for purging. This was confirmed in vivo by the survival of lethally irradiated recipients transplanted with purged simulated remission bone marrow (1 x 10(6) normal bone marrow cells and 5 x 10(4) leukaemic cells). A further increase of the therapeutic index cells was achieved by the alkyl-lysophospholipid ET-18-OCH(3). An incubation for 4 h at 37 degrees C with 25 microg/ml in the presence of 5% fetal calf serum preferentially enhanced the cytotoxic effect towards the leukaemic stem cell. The combination of AcSDKP and ET-18-OCH(3) with hyperthermia resulted in a therapeutic index of > 5000. This enabled a reduction of the hyperthermic treatment and will further minimize the toxicity to normal haematopoietic stem cell subsets, while a therapeutic index far above the required value is achieved. This tripartite purging treatment therefore offers a safe and fast purging protocol for the elimination of residual leukaemic cells in autografts.

Acute Disease↗
PubMed2000

1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine.

In this study, we show that an inhibitor of glycosphin-golipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increases the chemosensitivity of neuroblastoma tumor cells for Taxol and vincristine. At noneffective low doses of Taxol or vincristine, the addition of a noneffective dose of PDMP resulted in 70% cytotoxicity, indicating synergy. Such an effect was not observed for etoposide (VP16). PDMP caused an early (6 h) increase in ceramide (Cer) levels, but the excess Cer was metabolically removed in the long-term (96 h). However, upon incubation with PDMP in combination with Taxol, but not with etoposide, Cer levels remained elevated at 96 h. These results suggest that neuroblastoma cells are normally able to metabolically remove excess Cer, but lose this capacity upon exposure to microtubule modulating anticancer agents (Taxol or vincristine). In addition, PDMP treatment resulted in a decreased efflux of [14C]Taxol and [3H]vincristine from neuroblastoma cells, similar to treatment with PSC833 or MK571, suggesting an effect of PDMP on the transporter proteins P-glycoprotein and/or multidrug resistance protein. PDMP did not further reduce [14C]Taxol or [3H]vincristine efflux in PSC833-treated cells, although it did further diminish cell survival under these conditions. We conclude that a combined administration of nontoxic concentrations of PDMP and either Taxol or vincristine results in highly sensitized neuroblastoma cells. This appears to involve a sustained elevation of Cer levels, possibly in concert with increased drug accumulation.

Animals↗
PubMed2000

P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia.

Despite treatment with intensive chemotherapy, a considerable number of patients with acute myeloid leukemia (AML) die from their disease due to the occurrence of resistance. Overexpression of the transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP) 1 has been identified as a major cause of cross-resistance to functionally and structurally unrelated drugs. In the present study, the functional activity of P-gp and MRP was determined in 104 de novo AML patients with a flow cytometric assay using rhodamine 123 (Rh123) in combination with PSC833 and carboxyfluorescein (CF) in combination with MK-571. The results were compared with clinical outcome and with known prognostic factors. The functional activity of P-gp and MRP, expressed as Rh123 efflux blocking by PSC833 and CF efflux blocking by MK-571, demonstrated a great variability in the AML patients. A strong negative correlation was observed between Rh123 efflux blocking by PSC833 and Rh123 accumulation (r(s) = -0.69, P < 0.001) and between CF efflux blocking by MK-571 and CF accumulation (r(s) = -0.59, P < 0.001). A low Rh123 accumulation and a high Rh123 efflux blocking by PSC833 were associated with a low complete remission (CR) rate after the first cycle of chemotherapy (P = 0.008 and P = 0.01, respectively). Patients with both low Rh123 and CF accumulation (n = 16) had the lowest CR rate (6%), whereas patients with both high Rh123 and CF accumulation (n = 11) had a CR rate of 73%. AML patients with French-American-British classification M1 or M2 showed a lower Rh123 accumulation than patients with French-American-British classification M4 or M5 (P = 0.02). No association was observed between the multidrug resistance parameters and overall survival of the AML patients. Risk group was the only predictive parameter for overall survival (P = 0.003).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Regulation of spontaneous and TNF/IFN-induced IL-6 expression in two human ovarian-carcinoma cell lines.

Autocrine and paracrine production of interleukin-6 (IL-6) is considered to be involved in the ongoing proliferation of ovarian-cancer cells. In view of the variability in IL-6 expression between various ovarian-cancer cells, we questioned whether differences in IL-6-gene regulation might be observed in ovarian tumor cells with and without IL-6 expression. The CAOV-3 cell line spontaneously secreted IL-6, which was enhanced by tumor necrosis factor-alpha (877 +/- 89 vs. 8,452 +/- 1,762 pg/ml, x +/- sd, p < 0.01). The electrophoretic mobility shift assay (EMSA) demonstrated that basic IL-6 expression was associated with DNA binding of activator protein-1 (AP-1) and nuclear factor IL-6 (NF-IL6). Nuclear factor kappa-B (NF-KB), which consisted mainly of p65-NF-KB was induced in response to TNF-alpha stimulation. A2780 cells did not express IL-6, either spontaneously or after stimulation with TNF-alpha. EMSAs, showed spontaneous AP-1 but no NF-IL6 or NF-KB DNA binding. TNF-alpha stimulation enhanced AP-1 and induced NF-KB but no NF-IL6 DNA binding in these cells. NF-IL6 protein, however, was detected in nuclear extracts of these cells by Western blotting. In contrast, IL-6-promoter transfection studies showed no difference in promoter activation between CAOV-3 and A2780. This study reveals that differential IL-6-gene expression observed in ovarian-cancer cell lines is independent of NF-IL6 activation.

DNA, Neoplasm↗
PubMed1999

Leukemia-induced bone marrow depression: effects of gangliosides on erythroid cell production.

Bone marrow depression is a common feature in hematological malignancies or other bone marrow-involving cancers. The mechanism of this hemopoietic suppression resulting in pancytopenia and especially anemia has not been elucidated. Gangliosides can be shed by cancer cells. Therefore, we investigated the effects of exogenously added gangliosides on erythropoiesis in a human and murine in vitro system. A dose-dependent inhibition of murine colony-forming-unit-erythroid (CFU-E) and burst-forming-unit-erythroid (BFU-E) colony growth was observed. Furthermore the maturation of BFU-Es into CFU-Es was inhibited. The inhibition by gangliosides was not abolished by increasing the dose of erythropoietin (10 U/ml). FACS-analysis studies with human CD34+ cells cultured with gangliosides (GM3), erythropoietin (EPO) and stem cell factor (SCF) demonstrated a strong inhibition on cell growth. This resulted in a significantly higher percentage of immature cells (CD34+/GpA-, 24% vs. 3%), and a lower percentage of mature erythroid cells (CD34-/GpA+, 36% vs. 89%). Under these circumstances the effects on erythroid cell growth were much higher than on other cell lineages. The inhibitory effect of gangliosides isolated from acute lymphoblastic leukemic patients on in vitro erythropoiesis suggests that in vivo hemopoietic suppression might have its origin in the gangliosides present and probably shed by the malignant cells in the microenvironment and plasma. Our results show that gangliosides inhibit erythropoiesis in vitro at several stages of development, by a mechanism involving modulation of the maturation of erythroid cells.

Animals↗
PubMed1999

Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes.

In the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity. Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins. The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes. Transient overexpression of inactive mutants of either Raf-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059, we demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B. Interestingly, it was shown that NF-kappa B-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction with c-Jun protein. We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent activation of NF-kappa B transcriptional capacity. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Differential regulation of IL-6 promoter activity in a human ovarian-tumor cell line transfected with various p53 mutants: involvement of AP-1.

In human ovarian carcinomas, the p53 tumor-suppressor gene is frequently mutated. Interleukin-6 (IL-6) in these tumors is known to stimulate tumor-cell proliferation. In order to evaluate the effect of several p53 phenotypes on the IL-6 promoter activity, the human ovarian wild-type (wt)-p53 cell line A2780 was stably transfected with an empty plasmid (CMV) or (m)-175-, m-248- or m-273-p53. Electrophoretic mobility-shift assays revealed differences in activator protein-1 (AP-1) DNA-binding activity in the various clones. The CMV and m-273 clone had comparable amounts of AP-1. The m-175 clone displayed the least and m-248 the most pronounced AP-1 binding. Supershift analysis of AP-1/DNA complexes with antibodies against the AP-1 sub-units, c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunB, and JunD, revealed that the AP-1/DNA complexes in the various clones had different compositions. Fra proteins were basically present only in m-175 and m-248 AP-1. IL-6-promoter activity was evaluated in the presence and absence of the AP-1 binding site which showed that the m-175-transfected clone has a transcriptional suppressing AP-1, whereas the CMV and the m-273 clones have an activating AP-1. Exposure of the p53 clones to tumor-necrosis factor-alpha (TNF-alpha) clearly altered the AP-1/DNA complex composition. IL-6-promoter activity was enhanced by TNF-alpha irrespective of the presence of an AP-1 binding site, while the degree of activation differed in the various clones, being most pronounced in the m-175 and m-248 clones. The results demonstrate that the basic and activated IL-6-promoter activity is differently regulated in the various p53 clones, possibly due to alterations in the AP-1 composition.

DNA, Complementary↗
PubMed1999

Multidrug resistance protein MRP1, glutathione, and related enzymes. Their importance in acute myeloid leukemia.

Multidrug resistance (MDR), which is cross-resistance to structurally and functionally unrelated drugs such as anthracyclines, epipodophyllotoxins and vinca alkaloids, is a major cause of treatment failure in malignant disorders. Known mechanisms of MDR are overexpression of the ATP-dependent membrane proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP1), or an increased detoxification of compounds mediated by glutathione (GSH) or GSH related enzymes. MRP1 appeared to transport drugs conjugated to GSH and also unmodified cytostatic agents in presence of GSH. The relation between MRP1, GSH and enzymes involved in GSH metabolism or GSH dependent detoxification reactions recently has drawn a lot of attention. Coordinated induction of MRP1 and GSH related enzymes is reported in malignant cells after exposure to cytostatic agents. Besides MRP1, a number of MRP1 homologs are identified, named MRP2, MRP3, MRP4, MRP5 and MRP6. The relation between MDR and expression of these MRP1 homologs is currently under research.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Role of macrophage colony-stimulating factor in the differentiation and expansion of monocytes and dendritic cells from CD34+ progenitor cells.

The present study focused on whether it is possible to expand monocytic cells from CD34+ progenitor cells by using macrophage colony-stimulating factor (M-CSF) in the absence and presence of mast cell growth factor (MGF) and IL-6. It was demonstrated that CD34+ cells differentiate without expansion to functional mature monocytic cells in the presence of M-CSF or combinations of M-CSF plus IL-6 and MGF. A different response pattern was observed for the number of clonogenic cells. The addition of IL-6 or both IL-6 and MGF to M-CSF containing cultures resulted in significant higher numbers of colony-forming unit-macrophage (CFU-M) as tested in clonogenic and 3H-thymidine assays. Furthermore, M-CSF plus both IL-6 and MGF appeared to be the most potent combination to preserve the monocytic precursor in cell suspension culture assays. These results indicate that IL-6 and MGF in conjunction with M-CSF affect CD34+ cells especially at precursor level without distinct effect on the more mature stages. Secondly we studied whether M-CSF is only critical for the monocytic lineage or also affects dendritic cell (DC) development. Indeed, we were able to culture CD83+ DC from CD34+ progenitor cells in the presence of M-CSF in conjunction with TNF-alpha, IL-4, and MGF although their absolute number is almost threefold lower than the number of CD83+ cells yielded from GM-CSF plus TNF-alpha, IL-4, and MGF stimulated CD34+ cells.

Antigens, CD34↗
PubMed1999

Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura.

PURPOSE: To determine the value in diagnosis and treatment of mean platelet life, platelet production, and major sites of platelet destruction in patients with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Sternal or posterior superior iliac spine bone marrow aspiration was performed in 141 patients. Platelet kinetic studies with Indium-111 tropolonate labeled autologous platelets were utilized to determine platelet production. RESULTS: Two subgroups of patients could be defined. The first group (n = 81, 58%) had normal or increased platelet production and increased peripheral platelet destruction. These patients fulfilled the conventional criteria for ITP, including reduced platelet survival time (mean +/- SD, 1.6 +/- 1.4 days). Forty-eight (59%) of these patients had increased splenic sequestration and 30 (88%) of the 34 patients who underwent splenectomy had a complete or partial remission. The second group (n = 60, 42%) had decreased platelet production, with significantly greater platelet survival times (3.6 +/- 2 days, P <0.0001). In this group, the proportion of patients with complete or partial response to splenectomy (62%) was somewhat lower (P = 0.09). These patients mainly had ineffective platelet production in the bone marrow. CONCLUSIONS: Platelet kinetic studies suggest that ITP is a heterogeneous disease that comprises two subgroups. Further studies are needed to validate these findings and to determine their effect on the choice and outcome of therapy.

Adult↗
PubMed1999

Interleukin-6 production by activated human monocytic cells is enhanced by MK-571, a specific inhibitor of the multi-drug resistance protein-1.

1. The intracellular transport of leukotriene C4 (LTC4) in hematopoietic cells such as human monocytes is controlled by an ATP dependent carrier encoded by the multidrug resistance protein1 (MRPI) gene whose function can be blocked by the compound MK-571. Since LTs play a major role in control of cytokine expression in monocytes, we questioned whether blocking of the MRPI mediated function by MK-571 might affect cytokine production. 2. MK-571 strongly enhanced IL-6 expression at mRNA and protein level in lipopolysaccharide (LPS) and interleukin-1 (IL-1) stimulated human monocytes giving rise to 2.0+/-0.4 (x+/-s.d.) and 5.7+/-3.5 fold induction of IL-6 protein secretion. The increase in IL-6 secretion was accompanied by an enhanced phosphorylation of p38 but not of c-Jun-N terminal kinase. 3. The involvement of the kinase signalling pathways was further analysed by using SB203580 and PD98059, specific inhibitors of the p38 and ERK1/2 signalling route. MK-571 mediated upregulation of IL-6 in the presence of IL-1 was partially attenuated by SB203580 and PD98059. Electrophoretic mobility shift assays demonstrated that MK-571 did not affect the IL-1 induced DNA binding activity of Activator Protein-1 and Nuclear Factor-kappaB but rather enhanced the transactivational activity of an IL-6 promoter construct. Finally it was shown that the MK-571 mediated effects on IL-6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti-oxidant pyrrolidine dithiocarbamate (PDTC). 4. These results indicate that the membrane transporter MRP1 is involved in the regulation of IL-6 expression in activated human peripheral blood monocytes.

ATP-Binding Cassette Transporters↗
PubMed1999

Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia?

The clinical use of autologous marrow transplantation in acute myeloid leukemia (AML) has been hampered by the inability to collect adequate numbers of cells after remission induction chemotherapy and the notably delayed hematopoietic regeneration following autograft reinfusion. Here we present a study in which the feasibility of mobilizing stem cells was investigated in newly diagnosed AML. Among 96 AML patients, 76 patients (79%) entered complete remission. Mobilization was undertaken with low dose and high dose schedules of G-CSF in 63 patients, and 54 patients (87%) were leukapheresed. A median of 2.0 x 10(6) CD34+ cells/kg (range 0.1-72.0) was obtained in a median of three leukaphereses following a low dose G-CSF schedule (150 microg/m2) during an average of 20 days. Higher dose regimens of G-CSF (450 microg/m2 and 600 microg/m2) given during an average of 11 days resulted in 28 patients in a yield of 3.6 x 10(6) CD34+ cells/kg (range 0-60.3) also obtained following three leukaphereses. The low dose and high dose schedules of G-CSF permitted the collection of 2 x 10(6) CD34-positive cells in 46% and 79% of cases respectively (P = 0.01). Twenty-eight patients were transplanted with a peripheral blood stem cell (PBSC) graft and hemopoietic repopulation was compared with the results of a previous study with autologous bone marrow. Recovery of granulocytes (>0.5 x 10(9)/l, 17 vs 37 days) and platelets (>20 x 10(9)/l; 26 vs 96 days) was significantly faster after peripheral stem cell transplantation compared to autologous bone marrow transplantation. These results demonstrate the feasibility of PBSCT in the majority of cases with AML and the potential advantage of this approach with respect to hemopoietic recovery.

Acute Disease↗
PubMed1999

A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation.

In the present study we examined in more detail the dual role of the c-JUN N-terminal kinase (JNK) and p38 stress-activated protein kinase pathways in mediating apoptosis or cellular activation in hematopoietic cells. Growth factor deprivation of the erythroleukemic cell line TF-1 led to apoptosis which was associated with an enhanced activity of JNK and p38 and immediate dephosphorylation of the extracellular signal-regulated kinases (ERKs). Enhanced activity of p38 and JNK was not only observed during apoptosis but also in TF-1 cells stimulated with IL-1. IL-1 rescued TF-1 cells from apoptosis. In this case, the upregulation of p38 and JNK was associated with an enhanced activity of ERK. By using SB203580, a specific inhibitor of the p38 signaling pathway, it was demonstrated that p38 plays a pivotal role in the apoptotic process. SB203580 repressed the apoptotic process to a large extent. In contrast, PD98059, a specific inhibitor of the ERK pathway, counteracted the suppressive effects of SB203580 and IL-1 on the apoptotic process indicating that the protective effect of SB203580 and IL-1 might be the result of a shift in the balance between the ERK1/2 and p38/JNK route. This was also supported by experiments with TF-1 cells overexpressing the Shc protein that demonstrated a significantly lower percentage of apoptotic cells, which coincided with higher ERK activity. Finally, the IL-1 and SB203580-mediated effects were associated with an enhanced nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) binding activity, which could also be blocked by PD98059. These data demonstrate a dual function of the p38 pathway whereby other factors, such as ERK kinases, AP-1 and NF-kappaB, might determine the final cellular response.

Apoptosis↗
PubMed1999

Multiple myeloma related cells in patients undergoing autologous peripheral blood stem cell transplantation.

A high incidence of oligoclonal serum M-components is observed in multiple myeloma (MM) patients treated with autologous stem cell transplantation (ASCT). To determine whether these M-components are produced by myeloma clonally related cells or caused by an aberrant B-cell regeneration we analysed by semi-nested ASO-RT-PCR and DNA sequencing the immunoglobulin (Ig) variable genes (VH) obtained from bone marrow samples obtained before and after transplantation and peripheral blood stem cell (PBSC) samples from seven patients. Myeloma clonally related cells are identifiable by the expression of variant Ig heavy chain isotypes and were detected in two patients at presentation. No myeloma clonally related cells were found in post-transplantation samples (n = 7) in spite of the appearance of new serum M-components. However, in two cases we amplified sequences from post-transplantation bone marrow cells that were able to bind to the B-cell clone-specific CDR3 oligonucleotides but showed no further similarity regarding the VDJ rearrangement. These data indicate that serum oligoclonality post-transplantation is not caused by myeloma clonally related B cells but rather by the regenerating B-cell compartment.

Base Sequence↗
PubMed1999

Phase III efficacy study of interleukin-3 after autologous bone marrow transplantation in patients with malignant lymphoma.

We evaluated the efficacy of recombinant human interleukin-3 (rhIL-3) in reducing the number of platelet transfusions and major infections after autologous bone marrow transplantation (ABMT) in patients with malignant lymphoma. 198 patients with non-Hodgkin's lymphoma (NHL, n = 111) and Hodgkin's disease (HD, n = 87) were randomized to receive rhIL-3 10 microgram/kg/d (n = 130) or placebo (n = 68) for a maximum of 28 d after ABMT. Several well-known conditioning regimens were used. From day 1 after ABMT patients were treated with placebo or rhIL-3 at a dose of 10 microgram/kg/d by continuous i.v. infusion for 7 d and then by s.c. administration for 21 d or until platelet (50 x 109/l) and neutrophil (0.5 x 109/l) recovery had occurred. Treatment was completed in 54% of the patients in the rhIL-3 group versus 75% in the placebo group (P < 0.004). Adverse events were the main reason for premature discontinuation in the IL-3 group (23% IL-3 v 5% placebo). The median number of platelet transfusions was not significantly different between the IL-3 group and the placebo group (8.0 IL-3 v 6.0 placebo, P = 0.09). Platelet engraftment (>/= 20 x 109/l) was not significantly faster in the IL-3 group (28 d in the IL-3 and 27 d in the placebo group, P = 0.06) and the incidence of haemorrhagic complications was similar in both groups. In patients receiving the full intended dose of rhIL-3, platelet engraftment to >/= 20 x 109/l was delayed (P = 0.007). The median time to neutrophil engraftment was 23 d in the IL-3 and 25 d for the placebo group (P = 0.39). There was no difference in the incidence of major infections. We conclude that treatment with IL-3 has no clinical benefit in patients receiving ABMT for malignant lymphoma.

Bone Marrow Transplantation↗
PubMed1999

Plasma IL-8 and IL-6 levels can be used to define a group with low risk of septicaemia among cancer patients with fever and neutropenia.

The standard therapy for patients with fever and chemotherapy-related neutropenia is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of a defined group of patients at low risk for septicaemia would be of great advantage for these patients. In this study plasma interleukin-8 (IL-8) and interleukin-6 (IL-6) levels measured at start of fever (n = 72) could define a low-risk group of febrile patients with neutropenia due to chemotherapy. For this purpose we collected and analysed data on 72 fever episodes from 53 patients with chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72 episodes, 18 were classified as bacteraemia and/or clinical sepsis (sepsis group). The IL-6 and IL-8 plasma concentration were significantly increased in patients with chemotherapy-related neutropenia and fever due to bacteraemia versus fever of non-bacterial origin (P = 0.043 and P = 0.022 respectively). Logistic regression analysis, with sepsis as the outcome variable, revealed significant effects of age combined with either IL-6 or IL-8. Sepsis occurrence was lowest for patients <16 years and highest in patients between 16 and 50 years, and was higher in patients with increased IL-6 (P = 0.032) or IL-8 (P = 0.049). No significant effect of leucocyte count, C-reactive protein, sex or underlying malignancy at presentation was detected. The plasma IL-6 and IL-8 levels were fairly strongly correlated (Pearson r = 0.62). Using a cut-off value with 100% sensitivity, both IL-8 and IL-6 could define a low-risk group of neutropenic patients of 28% (CI 15-40%) at the start of the febrile period. Intervention studies are warranted to confirm this result and to investigate whether an early discharge based on IL-8 or IL-6 measurement is safe, increases the quality of life, and results in cost savings.

Adolescent↗
PubMed1999

Peripheral blood T lymphocytes from asthmatic patients are primed for enhanced expression of interleukin (IL)-4 and IL-5 mRNA: associations with lung function and serum IgE.

BACKGROUND: The TH2-like cytokines interleukin (IL)-4 and IL-5 play a pivotal role in airway wall inflammation in asthma and these cytokines are increased in peripheral blood and bronchoalveolar lavage fluid from asthmatic patients. It is unclear why specifically TH2-like cytokines are increased in asthmatic patients. A possible explanation may be an impaired adenylyl cyclase activity, which has been observed in peripheral blood mononuclear cells of asthmatics. OBJECTIVE: To assess interferon (IFN)-gamma, IL-4 and IL-5 mRNA expressions and their control by prostaglandin E2 (PGE2), which activates adenylyl cyclases, of peripheral T lymphocytes from patients with moderately severe asthma and healthy controls. METHODS: Peripheral blood T lymphocytes from asthmatics and healthy controls were isolated and stimulated with antibodies against CD3 plus CD28 in the absence and presence of increasing concentrations of PGE2. IFN-gamma, IL-4 and IL-5 mRNA levels were detected by reverse transcription-polymerase chain reaction. RESULTS: In contrast to IFN-gamma mRNA, IL-4 (P = 0.03, n = 8) and IL-5 (P < 0. 05, n = 5) mRNAs in the asthma group were significantly higher than in controls (n = 4). In addition, IL-5 showed a significant inverse correlation with forced expiratory volume (FEV1) (P < 0.04, n = 5), whereas IL-4 positively correlated with PC20adenosine-monophosphate (AMP) (P < 0.02, n = 8). Accumulation of mRNA for IFN-gamma, IL-4 and IL-5 mRNA were significantly diminished by 10-5 m PGE2 in both asthmatics and controls. In contrast, 10-6 m PGE2 significantly down-regulated IFN-gamma and IL-4 mRNAs (P < 0.05 for both IFN-gamma and IL-4, n = 4) in the control group, whereas this was not observed for IL-4 mRNA in the asthma group (n = 7). CONCLUSIONS: Activated peripheral blood T lymphocytes from asthma patients display higher levels of IL-4 and IL-5 mRNA in vitro, which may be due to a diminished activity of adenylyl cyclase. A new observation is that higher IL-4 mRNA levels are associated with less severe AMP responsiveness, which might be due to a negative feedback loop of IL-4 production by mast cells.

Adult↗