[Tumor necrosis factor].
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Drug Evaluation↗
Biomedical subjects
F Herrmann
Publications and source records attributed to F Herrmann.
Functional consequences of monocyte IL-2 receptor expression. Induction of IL-1 beta secretion by IFN gamma and IL-2.
The generation of an immune response involves the interaction of monocytes and T cells, but the events which regulate this interaction are not well understood. Culture of human peripheral blood monocytes in vitro induces low level surface expression of the p55 protein of the IL-2R and the expression of this receptor can be enhanced significantly by exposure to IFN-gamma. The addition of IL-2 to IFN-gamma-treated monocytes was shown to augment subsequent IL-1 beta secretion in the presence or absence of LPS. These effects could be partially blocked by anti-p55-IL-2R mAb. Nuclear "run on" assays and Northern analysis to probe for IL-1 beta transcripts showed enhanced IL-1 beta gene transcription and mRNA accumulation by monocytes treated with IFN-gamma and IL-2 but not in cultures that were obtained from monocytes treated with IL-2 alone. These results suggest that the T cell lymphokines IFN-gamma and IL-2 may act in a sequential fashion on monocytes to amplify the immune response by establishing a positive feedback circuit.
Adjuvants, Immunologic↗
Production of macrophage-, granulocyte-, granulocyte-macrophage- and multi-colony-stimulating factor by peripheral blood cells.
The specific cell sources and signals for induction of various colony-stimulating factors (CSF) in peripheral blood mononuclear cells (PBMC), purified T lymphocyte and monocyte (Mo) populations have been investigated. In the absence of exogenous activating stimuli, human PBMC, T cells and Mo failed to produce stable cytoplasmic mRNA for CSF for macrophages (M-CSF or CSF-1), for granulocytes (G-CSF), for granulocytes and macrophages (GM-CSF) and for multilineage CSF [multi-CSF, interleukin (IL) 3] and thus failed to release CSF proteins. However, after stimulation with phorbol myristate acetate and phytohemagglutinin, M-, G-, GM- and multi-CSF mRNA became detectable in PBMC, resulting in the secretion of the respective proteins. Identical culture conditions resulted in synthesis of only G- and M-CSF by purified Mo, whereas purified T lymphocytes produced GM-CSF and multi-CSF only. When Mo or T lymphocytes were exposed to recombinant human interferon-gamma or were stimulated by triggering the epitopes recognized by the monoclonal antibodies anti-Tll2 and Tll3, respectively, again disparate CSF expression patterns were found to be associated with both cell species. Moreover, IL2-receptive T lymphocytes showed the same distinct pattern of CSF secretion when activated by recombinant human IL2.
Colony-Stimulating Factors↗
Role of colony-stimulating factors in the biology of acute myelogenous leukemia.
A high proportion of acute myeloid leukemias (AML) recently investigated for their capacity to synthesize biologically active bioregulatory molecules was found to accumulate messenger (m) RNA and to produce membrane-bound or -secreted forms of stimulating factors for granulocyte, macrophage and mixed granulocyte-macrophage colony growth. Blast cells have also been found to secrete interleukin 1, tumor necrosis factor-alpha, interleukin 6, and to express receptors for various growth factors as well. However, growth factors like interleukin 2 and interleukin 3 have not been identified as AML products, and several other factors including interleukin 4, interleukin 5, etc. need further evaluation. Responsiveness of clonogenic leukemic cells to exogenous growth-promoting factors in vitro suggests a possible role of these biomolecules in the course of these disorders. Important evidence for the crucial role of growth factors, at least in some subtypes of AML, has been provided by demonstrating constitutive growth factor production by leukemic cells and their autonomous in vitro growth which is dependent on autocrine secretion of a specific growth factor. The concert of mechanisms providing stimulatory and inhibitory signals for hematopoiesis, which is adapted to the various physiological requirements of the organism, may have multiple defects in AML. This leads to successive steps of malfunctioning of cells, which finally express a fully malignant phenotype. In addition, these derangements also lead to defects in accessory cells on the level of mediator communication. However, there is evidence for autonomous growth promotion of AML blast by constitutive production of growth factors active in an autocrine fashion (GM-CSF, G-CSF, interleukin 6) and by recruitment of accessory cells to increase CSF supply (GM-CSF, G-CSF) via molecules such as interleukin 1 and TNF-alpha in a paracrine fashion. Molecular analysis of transformed hematopoietic cells has revealed changes of the genome, e.g., insertion of viral genetic information or cytogenetic fractures at DNA sites controlling growth factor gene activation. These events appear to be crucial in the induction of uncontrolled growth factor expression promoting oncogenic transformation of hematopoietic progenitor cells.
Colony-Stimulating Factors↗
Minimal peripheral blood cells carrying clonal markers of B cell disorders: evidence for monoclonality of circulating lymphocytes in patients with multiple myeloma.
Peripheral blood lymphocytes (PBL) of 20 patients with multiple myeloma (MM) were assayed for clonality by Southern blot and cell surface marker analysis. Eight samples showed monoclonal origin of circulating lymphocytes by demonstrating rearrangements of the heavy chain immunoglobulin gene (IgH). In selected experiments, comparison of IgH rearrangements of bone marrow plasma cells and peripheral blood-derived mononuclear cells, highly enriched for B lymphocytes, proved to be identical. However, monoclonal circulating cells could not be detected in samples with rearranged IgH genes by surface marker phenotyping using one-color immunofluorescence analysis and a panel of monoclonal and polyclonal antibodies to various B lineage-associated antigens. These results indicate that in a substantial proportion of MM, monoclonal growth involves circulating B lymphocytes and underscores the clinical usefulness of Southern analysis of IgH gene rearrangements for monitoring this disease.
Antibodies, Monoclonal↗
Monocyte interleukin-1 secretion is regulated by the sequential action of gamma-interferon and interleukin-2 involving monocyte surface expression of interleukin-2 receptors.
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Blotting, Northern↗
Polypeptides controlling hematopoietic cell development and activation. I. In vitro results.
Recombinant DNA technology has been central in answering some of the most relevant questions in the research of regulation of the functional status of hematopoietic progenitor cells and their progeny. This leading article will focus on recent results that have emerged from studies utilizing recombinant molecules that control hematopoietic blood cell development and activation. The following features will be detailed: The molecular and biological characteristics and biochemistry of hematopoietic growth factors, synergizing factors and releasing factors, their role in the regulation of hematopoiesis and activation of normal and leukemic cells, their cellular sources, and regulation of production.
Animals↗
Polypeptides controlling hematopoietic blood cell development and activation. II. Clinical results.
Colony-stimulating factors (CSFs) have entered the clinical arena. Several investigators have explored, in first clinical phase I studies, different routes of administration to define the optimum biological dose, maximum tolerated dose, toxicity, and pharmacokinetics of these reagents. It has been demonstrated that recombinant human (rh) granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF) can be safely administered over a broad dose range to increase number of circulating granulocytes in man. More recently, GM-CSF and G-CSF have been involved in phase Ib/II studies to assess the granulopoietic responses of patients with granulocytopenia due to various underlying disease states including myelodysplastic syndrome, aplastic anemia, cyclic neutropenia, Kostmann's syndrome, and the acquired immuno-deficiency syndrome. Both factors were also investigated with respect to their potential to prevent chemotherapy induced granulocytopenia or to accelerate recovery from that condition. The short-term effects of rh GM-CSF after autologous bone marrow transplantation for various solid tumors and lymphoid malignancies were assessed as well. In this article we will focus on recent results that have emerged from in vivo studies utilizing CSFs.
Bone Marrow↗
Lymphokine activated killer cells.
Various subpopulations of human leukocytes may be induced by lymphokines to exert cytotoxic activity. In man major histocompatibility complex non-restricted tumor cell lysis by interleukin-2 (IL-2) induced peripheral blood lymphocytes is attributed mainly to natural killer cells. These T cell receptor negative large granular lymphocytes are called lymphokine activated killer (LAK) cells. In order to explore the potential of LAK cells in tumor therapy, several clinical studies have been conducted, using IL-2 alone or in combination with ex vivo IL-2-activated peripheral blood lymphocytes. Objective responses have reproducibly been achieved only in renal cell carcinoma and malignant melanoma and were associated with considerable toxicity. In view of restricted efficacy and increasing doubts as to whether LAK cells indeed account for the in vivo observed responses, more recent strategies focus on tumor antigen specific cytotoxic T cells or tumor infiltrating lymphocytes. Successful translation of this approach into clinical practice, however, may be dependent on some basic problems of tumor immunology to be solved which were thought to be by-passed by the LAK cell approach.
Animals↗
Acute pancreatitis and normoamylasemia. Not an uncommon combination.
A consecutive series of 352 attacks of acute pancreatitis (AP) was studied prospectively in 318 patients. AP was ascertained by contrast-enhanced CT scan in all but four cases in which diagnosis was made at operation or autopsy. Sixty-seven of these cases (19%) had normal serum amylase levels on admission (i.e., less than 160 IU/L, a limit that includes 99% of control values), a figure considerably higher than generally admitted. When compared to AP with elevated serum amylase, normoamylasemic pancreatitis was characterized by the following: (1) the prevalence of alcoholic etiology (58% vs. 33%, respectively, p less than 0.01), (2) a greater number of previous attacks in alcoholic pancreatitis (0.7 vs. 0.4, p less than 0.01); and (3) a longer duration of symptoms before admission (2.4 vs. 1.5 days, p less than 0.005). In contrast AP did not appear to differ significantly in terms of CT findings, Ranson's score, and clinical course, when comparing normo- and hyperamylasemic patients, although there was a tendency for normoamylasemic patients to follow milder courses. Serum lipase was measured in 65 of these normoamylasemic cases and was found to be elevated in 44 (68%), thus increasing diagnostic sensitivity from 81% when amylase alone is used to 94% for both enzymes. A peritoneal tab was obtained in 44 cases: amylase concentration in the first liter of dialysate was greater than 160 IU/L in 24 cases (55%), and lipase was greater than 250 U/L in 31 cases (70%). Twelve of these 44 cases had low peritoneal fluid and plasma concentrations for both enzymes. Thus little gain in diagnostic sensitivity was obtained when adding peritoneal values (96%) to serum determinations. AP is not invariably associated with elevated serum amylase. Multiple factors may contribute to the absence of hyperamylasemia on admission, including a return to normal enzyme levels before hospitalization or the inability of inflamed pancreases to produce amylase. Approximately two thirds of cases with normal amylasemia were properly identified by serum lipase determinations. AP does not appear to behave differently when serum amylase is normal or elevated, and should therefore be submitted to similar therapeutic regimens in both conditions.
Acute Disease↗
Granulocyte-macrophage colony-stimulating factor induces cytokine secretion by human polymorphonuclear leukocytes.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known as an inducer of proliferation and functional activation of myeloid cells. This study was carried out to characterize the effects of GM-CSF on polymorphonuclear leukocytes (PMN) more extensively. Using Northern blot analysis, we show that PMN are able to accumulate mRNAs for different cytokines, including tumor necrosis factor-alpha (TNF-alpha); G-CSF, and M-CSF, all of which are involved in inflammation and hematopoiesis. Biological assays and immunoassays demonstrate that PMN translate these mRNAs, except TNF-alpha, into secretory proteins. However, the expression of these cytokines is dependent on stimulation by exogenous signals, preferentially provided by the T cell-derived lymphokine GM-CSF. Stimulation of hematopoiesis and amplification of defense mechanisms after T cell activation thus might involve not only monocytes but also PMN, a cell type previously believed to be biosynthetically inactive.
Animals↗
Participation of the cytokines interleukin 6, tumor necrosis factor-alpha, and interleukin 1-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control.
Autonomous in vitro growth of myeloid leukemic colony-forming cells may in part result from autocrine production of colony-stimulating factors (CSF). Some acute myeloid leukemia (AML) samples, however, fail to synthesize CSF despite growing autonomously in agar, and are therefore believed to bypass CSF requirements. Cytokines such as IL-6, tumor necrosis factor (TNF)-alpha, and IL-1, products of cells of the myeloid lineage, are known to be involved in growth control of myeloid progenitor cells. Since these molecules may also contribute to autocrine and paracrine growth regulation of myeloid leukemias, we screened a series of AML for cytokine production. In addition, possible roles of IL-6, TNF-alpha, and IL-1 in growth control of AML were investigated in vitro. We show that a substantial proportion of AML cells produce IL-6, TNF-alpha, and IL-1-beta and use these mediators to stimulate their growth by disparate mechanisms: IL-6 acts as a costimulator to enhance CSF-induced clonogenicity of AML blasts. TNF-alpha induces CSF production by endothelial cells and may therefore provide a paracrine loop to support leukemia growth.
Colony-Stimulating Factors↗
Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor.
The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) was investigated in 30 patients with advanced malignancy in a phase Ib trial. Patients were treated at four different dose levels (120 to 1,000 micrograms/m2/d) by either daily intravenous (IV) bolus injection or 24-hour continuous infusion. Administration of rh GM-CSF resulted in a broad spectrum of dose- and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total 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 five days 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 rapidly reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnea, and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules used 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 number and function of leukocytes in vivo may prevent neutropenia and infections when GM-CSF is added to cytotoxic cancer therapy.
Adolescent↗
Interleukin-4 induces secretion of CSF for granulocytes and CSF for macrophages by peripheral blood monocytes.
T cells are known to interact cooperatively with monocytes to produce Colony-Stimulating Factors (CSF), although T cell-mediated signals leading to CSF secretion by monocytes are not completely understood. We have made use of Northern blot hybridization and specific bioassays to study the effects of the T cell product interleukin-4 (IL-4) on monocyte CSF expression. The results suggest a previously unrecognized role of IL-4 as a CSF inducer since exposure of monocytes to IL-4 resulted in accumulation of transcripts for granulocyte-CSF (G-CSF) and macrophage-CSF (M-CSF). Consequently, IL-4-activated monocytes released factors in their culture supernatants biologically and antigenically indistinguishable from G- and M-CSF.
Animals↗
Hematologic effects of recombinant human granulocyte colony-stimulating factor in patients with malignancy.
The effect of recombinant human granulocyte colony-stimulating factor (G-CSF) on hematologic parameters was evaluated in a phase I clinical study in 18 patients with advanced malignancy. G-CSF was administered once daily as a 30-minute infusion for 14 days; three patients each were treated at increasing dose levels of 1, 3, 10, 30, and 60 micrograms kg-1 day-1. A transient decrease in neutrophil and monocyte counts was observed immediately after the G-CSF infusion, followed by a dose-dependent increase of up to 15-fold. G-CSF-induced neutrophils exhibited an increased O2- radical production, and serum levels of enzymes related to granulocyte turnover, including lysozyme and elastase, were markedly elevated during therapy. A dose-dependent depression of platelet counts occurred in the second third of the treatment course, followed by a spontaneous recovery despite continuing therapy. G-CSF was well-tolerated; minor to moderate bone pain was the most common side effect. The primary course of the malignant diseases studied was not significantly altered. G-CSF appears to be an appropriate means to selectively increase the number of functionally competent polymorphonuclear phagocytes.
Adult↗
[Trichomonas vaginalis infection in pregnant women and newborn infants].
We studied 149 pregnant women at delivery and 113 newborns in order to determine the frequency of T vaginalis infection. Neutral red stain, dark field microscopy and culture methods were used with comparable yields. The age of women ranged from 12 to 43 years. A 27.5% infection rate was detected in mothers but all newborns were free from infection. Infection rates in relation to age among mothers confirmed previously reports.
Adolescent↗
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↗
[Comparison of three histometric methods for the comprehension of stimulating effects on the rat thyroid gland].
There exist some histometric methods for the morphological quantification of different strongly stimulating effects on the thyroid gland induced by drugs and/or other chemical substances in dependence upon dose and duration of application. But in respect of technical and temporal expense and also diagnostic statement, there are considerable differences between these recording procedures. Therefore we examined the 3 mostly used methods synchronously (i.e. determination of thyroid epithelial cell height, nuclear volume in thyrocytes, and estimation of relative volume parts in the thyroid gland by the point counting method) by investigating the thyroid glands of methylthiouracil-(MTU)-stimulated rats and corresponding controls in order to compare the diagnostic value and temporal expense. The largest temporal expense was required in the nuclear volume determination, the smallest in the point-counting method. On principle, all 3 procedures allow the determination of hypertrophic alterations but only by help of the point-counting method, also hyperplastic changes are recognizable. By nuclear volume determination, we found significant differences between central and peripheral parts of the thyroid gland. Therefore, to avoid the subjective error, it will be necessary to measure a large number of nuclei in many planes of the gland. Also the determination of epithelial cell high reinforces the subjective error because of the heterological structure especially in unstimulated thyroid gland. If the number of counting points is exactly determined and, full of sense, limited, the point-counting method allows a nearly complete measuring of the whole object to be tested within an acceptable investigation time. In this way, the heterological structure of thyroid gland will be regarded, and comparability and reproducibility are guaranteed on an high level.
Animals↗