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Biomedical subjects

A Lindemann

Publications and source records attributed to A Lindemann.

At least 145 records · Page 8Linked to original sources
PubMed1989

Interleukin-2 and interferon-gamma recruit different subsets of human peripheral blood monocytes to secrete interleukin-1 beta and tumour necrosis factor-alpha.

Exposure of cultured human peripheral blood monocytes (PBMO) to interferon-gamma (IFN-gamma) enhances surface expression of the p55 subunit of the interleukin-2 receptor (IL-2R). Addition of IL-2 to IFN-gamma treated monocytes will stimulate subsequent release of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) due to enhancement of the transcriptional rate and stability of mRNA accumulation of both genes. The present study was aimed to investigate whether IFN-gamma and IL-2 will favour the release of IL-1 beta and TNF-alpha by different subsets of human PBMO. To this end PBMO were separated into four fractions with densities ranging from 1.058 to 1.075 kg/l by means of discontinuous bovine serum albumin (BSA) gradient centrigugation. Following incubation of monocyte subsets in the presence or absence of IFN-gamma and IL-2 for a culture period of 24-48 h, cell-free culture supernatants were collected and assayed for IL-1 beta and TNF-alpha activity by ELISA. Surface p55 IL-2R expression was detected by CD25 monoclonal antibody (MoAb) anti-IL-2R1 using immunofluorescence analysis. Although IL-2R1 expressing PBMO were equally distributed among the four fractions, IL-1 beta secretion was found to reside mainly in the most dense fraction. The major TNF-alpha activity was detected, however, in supernatants obtained from cultures of PBMO with densities of 1.065-1.075 kg/l. These data demonstrate functional heterogeneity of subsets of human PBMO with respect to their capacity to produce distinct cytokines.

Cells, Cultured↗
PubMed1989

Granulocyte-macrophage colony-stimulating factor (CSF) and multilineage CSF recruit human monocytes to express granulocyte CSF.

We assessed the capacity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and multilineage (Multi)-CSF to induce release of granulocyte-CSF (G-CSF) by highly purified peripheral blood monocyte (Mo) preparations. Our results reveal that GM-CSF and Multi-CSF, either alone or in a synergistic concert, activate Mo to transcribe G-CSF messenger (m) RNA and release biologically active G-CSF protein into their culture supernatants. G-CSF had no regulatory effect on Mo expression of cytoplasmic G-CSF mRNA levels and G-CSF protein secretion by itself. These differential actions of CSFs provide further insight into self-regulatory mechanisms within the growth factor hierarchy system.

Cell-Free System↗
PubMed1989

Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome with excess blasts.

As part of a broad phase I study of recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF), four patients were treated who had myelodysplastic syndrome (MDS) with excess blasts. The GM-CSF was given daily as an intravenous injection over a period of 30 min for 5 days. A total of 11 cycles were conducted. Each patient received at least two different dose levels. In three patients, three different dosages were delivered. The treatment course was interrupted by a 10-day rest period. Rh GM-CSF was well tolerated, with only minor side effects seen, which included bone discomfort at the lower back, sternum and ribs, and constitutional symptoms such as low grade fever, nausea/vomiting, and mild myalgias. Whereas no increases in platelet and reticulocyte counts were recorded, elevations of absolute neutrophil counts above 100 cells/microliters occurred in all patients. The most striking finding was, however, the development of increases in the number of circulating and bone marrow blast counts that were observed particularly when doses of greater than or equal to 500 micrograms/m2 of body surface area were administered. In line with data demonstrating in vitro induction of proliferation of leukemic blast cells by rh GM-CSF, one may take advantage of blastogenesis induced in vivo that may favor the use of a therapeutic strategy by recruiting quiescent cells into the mitotic cycle which would then represent optimum targets for a subsequent cycle-specific cytotoxic chemotherapy. Such an approach could form the basis for new clinical trials in MDS.

Adult↗
PubMed1989

High-level secretion of tumor necrosis factor-alpha contributes to hematopoietic failure in hairy cell leukemia.

Hairy cell leukemia (HCL) is frequently associated with severe pancytopenia. The authors detected high levels of tumor necrosis factor (TNF)-alpha in the bone marrow serum of patients with HCL and found anti-TNF-alpha neutralizing monoclonal antibodies (MoAbs) to be able to enhance hematopoiesis of HCL patients in in vitro colony assays. As potent producers of TNF-alpha, hairy cells could be identified, thus implicating the malignant population in the pathogenesis of hematopoietic failure due to inappropriate secretion of this cytokine.

Hematopoietic System↗
PubMed1988

Granulocyte/macrophage colony-stimulating factor induces interleukin 1 production by human polymorphonuclear neutrophils.

The purpose of this study was to determine whether human polymorphonuclear neutrophils (PMN), which share a common cell lineage with macrophages, could produce factors such as IL-1. We show by Northern blot analysis and bioassays that PMN can be induced to accumulate mRNA specific for IL-1 alpha and IL-1 beta indistinguishable in size from IL-1 mRNA synthesized by activated human macrophages and consequently to release IL-1-like activity in their culture supernatants, that could be neutralized by a mAb to IL-1. The granulocyte-macrophage colony-stimulating factor was identified as a major physiologic inducer for PMN-IL-1.

Animals↗
PubMed1988

Recombinant human granulocyte-macrophage colony-stimulating factor induces secretion of autoinhibitory monokines by U-937 cells.

Colony-stimulating factors are required for survival proliferation, differentiation and functional activation of granulocytes, macrophages and their precursor cells. In the present report, however, we demonstrate antiproliferative activity of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) on monoblast cell line U-937 and provide evidence for the involvement of tumor necrosis factor alpha TNF-alpha and interleukin 1 beta (IL 1 beta) in its growth inhibitory action. GM-CSF (but not granulocyte CSF, G-CSF or macrophage CSF, M-CSF) suppressed DNA synthesis and self renewal of U-937 cells. Similarly, medium conditioned by U-937 cells in response to GM-CSF (GM-CSF U-937-CM) was able to reduce clonogenicity and [3H]thymidine uptake by U-937 cells. Since neutralization of GM-CSF present in GM-CSF U-937-CM by monoclonal antibody to GM-CSF did not abrogate the autoinhibitory activity present in GM-CSF U-937-CM, we considered the possibility that other soluble molecules are released by U-937 cells upon GM-CSF stimulation. Neutralization by antibodies to IL 1 beta and TNF-alpha suggested that both monokines could be the antiproliferative principle operating in GM-CSF U-937-CM. Moreover, employing IL 1 beta-specific enzyme-linked immunosorbent assay, TNF-alpha specific radioimmunoassay, Northern analysis using a cloned TNF-alpha-specific cDNA and an oligonucleotide probe for IL 1 beta, we demonstrate GM-CSF-inducible IL 1 beta and TNF-alpha gene expression by U-937 cells at the mRNA and protein level. Although M-CSF expression was induced under similar conditions, M-CSF failed to inhibit growth of U-937 cells.

Adult↗
PubMed1988

The suppressive effects of recombinant human tumor necrosis factor-alpha on normal and malignant myelopoiesis: synergism with interferon-gamma.

The modulation of growth of normal and leukemic myeloid progenitor cells in soft agar cultures by recombinant human tumor necrosis factor-alpha (TNF alpha) and recombinant human interferon-gamma (IFN gamma) was investigated. TNF alpha inhibited colony formation of all colony types representing different maturational stages of normal progenitor cells committed to the myeloid lineage with different orders of sensitivity. Blast-type colonies derived from patients with acute myelogenous leukemia were more sensitive to TNF alpha inhibition than progenitor cells purified from normal bone marrow or bone marrow from patients with stable-phase chronic myelogenous leukemia. The response of most colony types to IFN gamma was poor. However, when IFN gamma was administered together with TNF alpha, synergistically enhanced antiproliferative effects were detected in all colony types tested. The antiproliferative action of IFN gamma on myelopoiesis was enhanced in culture by the presence of autologous monocytes, presumedly by inducing endogenous production of TNF alpha. However, TNF alpha seemed to act directly on the progenitor cells themselves to suppress their clonal growth, rather than involving accessory marrow elements such as monocytes and/or T lymphocytes.

Antibodies, Monoclonal↗
PubMed1988

Maternal levels of pregnancy-specific beta 1-glycoprotein (SP-1) are elevated in pregnancies affected by Down's syndrome.

Concentrations of pregnancy-specific beta 1-glycoprotein (SP-1) were measured in maternal blood and amniotic fluid of patients with a trisomic fetus and compared with that of a cytogenetically normal fetus at weeks 16-19 of pregnancy. The SP-1 concentrations were significantly elevated in the sera of women with a Down's syndrome fetus, whereas amniotic fluid levels were only slightly increased. It is suggested that high levels of maternal SP-1 in the second trimester of pregnancy may be a valuable indicator in the prenatal detection of fetal trisomy 21.

Amniotic Fluid↗
PubMed1988

Incidence of lineage promiscuity in acute myeloblastic leukemia: diagnostic implications of immunoglobulin and T-cell receptor gene rearrangement analysis and immunological phenotyping.

Sixty-nine blood or bone marrow samples from both children and adults with acute myeloblastic leukemia (AML) were investigated to elucidate the frequency of immunoglobulin (IG) and T-cell receptor (TCR)-gene rearrangements. Non-germline configuration for the IG heavy chain (h) gene was detected in the specimens of nine patients of various subtypes according to the French-American-British classification (FAB), including FAB M1, M2, M4 and M5. Rearrangement of the IG kappa chain (k) gene was present in one of these cases which simultaneously revealed a rearranged TCR-beta (b) chain gene. In another two AML samples we found TCR-b gene rearrangements, in one case in combination with an IG-h gene rearrangement. IG-h gene rearrangements were detected in 10 cases, in one case in conjunction with an IG-kappa (k) and TCR-b gene rearrangement. A highly significant correlation between the occurrence of DNA rearrangements of the IG-h locus and nuclear staining with the enzyme terminal deoxynucleotidyl transferase (TdT) and surface expression of the CD 19 and CD 34 antigen could be identified: all 10 TdT positive AML samples rearranged IG-h. Similarly, six out of 69 AML samples exhibited surface expression of CD 19, five of these in combination with CD 34 and all of them rearranged the IG-h gene. The one leukemia with TCR-b gene rearrangement only was TdT positive as well, but did not express CD 19 or CD 34. We conclude that IG-h gene is rearranged in a substantial proportion of AML, strongly associated with a specific immunophenotype (TdT+, CD19+, CD34+), whereas TCR-b gene rearrangement appears more rarely. No positive correlation between occurrence of IG-h and TCR-b gene-rearrangements and one AML FAB-subtype was found, although a clustering of M1 and M4 FAB subtypes in the AML group showing reconstructed IG-h gene became evident.

Adult↗
PubMed1988

Interleukin 1 stimulates T lymphocytes to produce granulocyte-monocyte colony-stimulating factor.

T lymphocytes are thought to cooperatively interact with monocytes to produce colony-stimulating factors (CSF). However, little is known about monocyte-mediated signals leading to CSF-secretion by T lymphocytes, although soluble monocyte products have been implicated. We have employed monoclonal antibody anti-T3B covalently coupled to CnBr-activated Sepharose 4B beads, to show that multimeric ligation of T cell antigen receptor leads to T cell receptiveness to interleukin 1 (IL-1), as indicated by T cell production of CSF, which induces growth of myeloid progenitor cells into neutrophil, eosinophil, and monocyte colonies. To investigate the molecular basis of these findings, total RNA was extracted from T3B Sepharose-primed and IL-1-stimulated T lymphocytes and probed for granulocyte-monocyte-CSF (GM-CSF), granulocyte-CSF (G-CSF), and monocyte-CSF (M-CSF) mRNA. GM-CSF, but not G-CSF or M-CSF, messages were detected. Nuclear "run on" assays revealed that IL-1 action is effective primarily at the level of GM-CSF gene transcription. These results suggest a previously unrecognized role of IL-1 in the regulation of GM-CSF secretion by T cells.

Colony-Stimulating Factors↗
PubMed1988

[Cytokines in tumor therapy].

The use of recombinant cytokines offers a new dimension in cancer treatment. While the effects of cytotoxic chemotherapy are relatively nonspecific and affecting all rapidly proliferating tissues, these hormone-like, physiologically produced substances are able to modulate tumor-host interactions and in addition may interact with pathogenetically relevant disturbances in growth related cellular functions. The latter principle seems to be of major importance for the impressive results of interferon alfa treatment in hairy cell leukemia. The expected anti-tumor effects of tumor necrosis factor alfa and of interleukin-2 activated killer cells, however, have only been observed in occasional patients, most of them with rare tumors. A more immediately promising therapeutic approach seems to be at hand with the hemopoietic growth factors. They are able to stimulate the non-specific system of host defense as well as the hemopoietic progenitor cell compartment, relevant for reconstitution after aplasiogenic chemotherapy and bone marrow transplantation and thus in near future could be of great importance in the treatment of tumor diseases.

Growth Substances↗
PubMed1988

Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: a phase ib clinical study.

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was investigated in 29 patients with advanced malignancy in phase Ib trial. Patients were treated at six different dose levels (30-1000 micrograms/m2/day) with either daily intravenous bolus injection or 24 hours continuous infusion for 5 days or 2 weeks. Administration of rh GM-CSF resulted in a broad spectrum of dose-, route-, and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total white blood cell (WBC) count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets and reticulocytes was not induced. Within one week after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnoea and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules employed and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase turnover and function of leukocytes in vivo may prevent neutropenia and infections, when GM-CSF is adjunctively added to cytotoxic cancer therapy.

Adult↗
PubMed1988

Regulation of gene expression of M-, G-, GM-, and multi-CSF in normal and malignant hematopoietic cells.

Colony stimulating factors (CSFs) are produced by a variety of cell types, including T-lymphocytes (T cells) and mononuclear phagocytes; both cell types are known to cooperatively interact to elaborate CSFs, although the specific cellular source of CSF species and mechanisms of intercellular communications in this regard are poorly understood. In this report, we investigate the specific origin of various CSF species in peripheral blood mononuclear cells (PBMC), purified T-lymphocyte and monocyte (Mo) populations. Furthermore, we assess the conditions required for stimulation of purified cell cultures to express CSF messenger RNAs (mRNAs) and proteins. In the absence of exogenous activation stimuli, human PBMC, T cells and Mo failed to produce transcripts for CSF for macrophages (M-CSF or CSF-1), for granulocytes (G-CSF), for granulocytes/macrophages (GM-CSF), and for multilineage CSF (multi-CSF or Il-3). However, after stimulation with phorbol myristate acetate (PMA) and phytohemagglutinin (PHA), mRNAs for M-, G-, GM-CSF, and multi-CSF became detectable in PBMC as early as 6 hours after initiation of cultures. Identical culture conditions resulted in synthesis of G-, and M-CSF mRNA by Mo, whereas T-lymphocytes produced GM-CSF and multi-CSF mRNA. More physiologically, when Mo were activated with interferon (IFN)-gamma or tumor necrosis factor-alpha (TNF-alpha) and T-lymphocytes were stimulated in an Mo-independent pathway, that is via triggering of the 50 kd sheep erythrocyte receptor protein employing monoclonal antibodies (mo ab) to the Tll-2- and Tll-3- defined epitopes, similar kinetics of mRNA expression were obtained. Similarly, when interleukin-1 (Il-1) receptive T cells were stimulated with Il-1, T cells transcribed functionally active GM-CSF and multi-CSF. Maximum peak activity of GM-, G-, and M-CSF protein secretion was identical for all CSF species investigated, and occurred in culture 48-72 hours after specific induction. Constitutive expression of CSFs not found in unactivated normal hematopoietic cells was, however, frequently observed in blast cell populations of patients with acute myeloblastic leukemia. Of 49 AML samples, 15 revealed G-CSF transcripts; 11, GM-CSF mRNA; and 6 samples synthesized M-CSF mRNA. Employing specific bioassays, 12 of 15 G-CSF-mRNA-producing cell populations, 8 of 11 GM-CSF-mRNA-producing cell populations, and 1 of 6 M-CSF-mRNA-synthesizing samples, demonstrated release of the respective functionally active CSFs into their culture supernatants.(ABSTRACT TRUNCATED AT 400 WORDS)

Blotting, Northern↗
PubMed1988

Constitutive expression of hematopoietic growth factor genes by acute myeloblastic leukemia cells.

Blast cell populations of forty nine individuals with acute myeloblastic leukemia (AML) were investigated for constitutive expression of genes for various hematopoietic growth factors. Fifteen samples constitutively exhibited messenger (m) RNA for colony stimulating factor for granulocytes (G-CSF). Eleven AML specimens produced mRNA specific for CSF for granulocyte and macrophages (GM-CSF). When probed for CSF for macrophages (M-CSF or CSF-1) specific hybridization signals became detectable in six samples. Five out of six blast cell populations transcribing M-CSF, synthesized G-, and GM-CSF mRNA's simultaneously, whereas another five leukemias transcribed G-, and GM-CSF genes exclusively. Furthermore, when specific bioassays were performed to detect secretion of biologically active CSF proteins by these leukemic blast samples, twelve out of fifteen G-CSF mRNA producing cell populations, eight out of eleven GM-CSF mRNA producing cell populations and one out of six M-CSF mRNA synthesizing samples, demonstrated release of the respective, functionally active CSF's into their culture supernatants. Our results show that gene transcription and protein secretion of hematopoietic growth factors are features that are frequently detected in leukemic myeloid blast cells and involve G-, GM-, and M-CSF. With respect to recent findings of receptiveness of leukemic colony forming cells (L-CFC) for proliferative stimuli provided by various hematopoietic growth factors, our findings point out a potential role of autocrineously produced CSF's in the pathophysiology of autonomous proliferation in AML.

Blotting, Northern↗
PubMed1987

Tumor necrosis factor (TNF)-alpha but not TNF-beta induces secretion of colony stimulating factor for macrophages (CSF-1) by human monocytes.

Tumor necrosis factor (TNF)-alpha has been identified as a major inducer of colony stimulating factor (CSF)-secretion by human vascular endothelial cells and fibroblasts. In the present study we assessed the capacity of TNFs to induce release of CSF-1 from highly purified peripheral blood monocyte preparations. Whereas monocytes do not accumulate CSF-1 messenger (m)RNA constitutively and consequently do not produce CSF-1 protein, CSF-1 mRNA and protein secretion became detectable, when monocytes were cultured in the presence of TNF-alpha, that was synergistically enhanced by interferon-gamma (IFN-gamma). However, under identical experimental conditions TNF-beta failed to induce monocyte CSF-1 synthesis. Cultures of monocytes in the presence of TNF-beta before addition of TNF-alpha abolished the CSF-1 inducing capacity of TNF-alpha, suggesting that TNF-beta may act as antagonist to TNF-alpha for CSF-1 production. These data point out a previously unrecognized function of TNF-alpha to modulate CSF-1 release by monocytes and demonstrate disparate biological properties of different TNF species in hematopoiesis.

Colony-Forming Units Assay↗