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Biomedical subjects

A Lindemann

Publications and source records attributed to A Lindemann.

At least 127 records · Page 7Linked to original sources
PubMed1990

In vivo recruitment of GM-CSF-response myelopoietic progenitor cells by interleukin-3 in aplastic anemia.

Previous studies have indicated that colony-stimulating factors may stimulate myelopoiesis and thus increase the number of circulating white blood cells in patients with hematopoietic failure including aplastic anemia. However, long-term administration of the factor was required to maintain its response. In the present article we report on a patient with severe aplastic anemia undergoing treatment with recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF). After an initial response, the patient became refractory to GM-CSF. However, treatment with interleukin (IL)-3 restored responsiveness to GM-CSF, suggesting that IL-3 may have replenished the bone marrow with myelopoietic progenitor cells sensitive to the action of GM-CSF. This observation suggests the value of application of sequentially acting hematopoietic growth factors in aplastic anemia patients.

Anemia, Aplastic↗
PubMed1990

Stimulation of granulopoiesis in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor: assessment of two routes of administration.

We administered Escherichia coli-derived recombinant human granulocyte-macrophage colony-stimulating factor to 61 patients with malignancy, 36 of whom had normal peripheral blood counts and 25 of whom had peripheral cytopenia due to underlying bone marrow disease, to compare the efficacy of two different routes of administration to stimulate the in vivo granulopoiesis: i.e., continuous i.v. infusion and s.c. injection. Three well-tolerated dose levels were investigated. Application of granulocyte-macrophage colony-stimulating factor resulted in dose-dependent increases in circulating neutrophils, eosinophils, and monocytes and an increase in bone marrow cellularity, irrespective of route of administration. In some patients, mild side effects, including bone pain, dyspnea, flu-like symptoms, and a decrease of platelet counts, were recorded, but they were less pronounced when the hormone was administered subcutaneously.

Adolescent↗
PubMed1990

Hematopoietic growth factors in oncology.

Hematopoietic growth factors, or hemopoietins, are peptide hormones produced by peripheral blood cells, bone marrow stroma, as well as several other cell types, such as endothelial cells and fibroblasts. Hemopoietins play a central role in regulating peripheral blood cell number and function. By recombinant DNA technology, several of these factors, also called colony-stimulating factors (CSF) or interleukins, are now available in such quantities to allow clinical evaluation. First experiences in clinical trials show that these peptides are capable of stimulating production of various cell types of the peripheral blood by stimulation of bone marrow progenitor cells without significant toxicity for the patient under treatment. Treatment of renal anemia by erythropoietin and reduction of chemotherapy-induced myelosuppression by G- and GM-CSF are already defined indications for these hemopoietins. Further studies are under way to test the indication of these factors in other clinical situations as well as studies investigating the biology, pharmacology, and clinical efficacy of interleukin 3 (IL-3).

Hematopoietic Cell Growth Factors↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

A phase-II study of low-dose cyclophosphamide and recombinant human interleukin-2 in metastatic renal cell carcinoma and malignant melanoma.

Recent preclinical and clinical studies that have demonstrated antitumor activity of high-dose recombinant interleukin-2 (rIL-2), and animal models that demonstrated a synergistic effect of low-dose cyclophosphamide, led us to study rIL-2 (Cetus Corp., Emeryville, Calif) in a phase II clinical trial in combination with low-dose cyclophosphamide in 32 patients, 18 with malignant melanoma and 14 with renal cell carcinoma. rIL-2 was given once daily at 3 x 10(6) U/m2, as a 30-min infusion for 14 days in cycle I and for 2 x 5 days in cycles II and III respectively; if tolerated, the dose was increased to a maximum of 6 x 10(6) U m-2 day-1; the cycles, separated by 1 week treatment-free intervals, were preceded each by a single i.v. bolus of cyclophosphamide at 350 mg/m2. The most prominent side-effects encountered in this trial consisted of a capillary leak syndrome, myalgia and fever that required dose reduction during the first cycle in one-half of the patients. Given the limit of tolerable toxicities in a standard care unit, the regimen employed achieved minor antitumor activity. No remission was achieved in patients with renal cell carcinoma, and 15% of melanoma patients showed objective responses (partial response + minor response).

Adult↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

A multicenter trial of interleukin-2 and low-dose cyclophosphamide in highly chemotherapy-resistant malignancies.

The anti-tumor activity of high-dose recombinant interleukin-2 (IL-2) has been demonstrated in several recent preclinical and clinical studies. In an attempt to study possible synergistic effects with low-dose cyclophosphamide (CYC), a phase II clinical trial was initiated in 32 patients, 18 with malignant melanoma (MM) and 14 with renal cell carcinoma (RCC). The recombinant IL-2 (Cetus Corp., Emeryville, Ca, U.S.A.) was given once daily at 3 x 10(6) U/m2, as a 30-min infusion for 14 days in cycle I and for five days twice in cycles II and III, respectively; if tolerated, the dose was escalated to a maximum of 6 x 10(6) U/m2/day; the cycles, separated by 1-week treatment-free intervals, were each preceded by a single i.v. bolus of CYC at 350 mg/m2. The most prominent side-effects encountered in this trial consisted of a capillary leak syndrome, myalgia and fever requiring dose reduction in half of the patients during the first cycle. Given the limit of tolerable toxicities in a standard care unit, the regimen employed achieved minor anti-tumor activity. No objective responses were achieved in patients with RCC and a 15% remission rate (PR + MR) was seen in melanoma patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

[Mechanism of resistance to tumor necrosis factor].

To find clues as to the possible mechanisms of resistance against the cytotoxic activity of tumor necrosis factor (TNF), we developed TNF-resistant and TNF-sensitive subclones of the human cervic carcinoma cell line ME 180 and the mammary carcinoma cell line BT-20. Resistant subclones were selected by gradually increasing the TNF concentration in the culture medium over 4 months or 20 passages. Resistance to TNF was conserved in the absence of TNF after nearly 3 years and less than 100 passages. There were no differences in the number and affinity of TNF receptors between the sensitive and resistant clones. Similarly, SDS-PAGE of cell lysates showed identical bands. Sensitivity to actinomycin D, mitomycin C, and interferon-gamma was the same. No TNF message could be demonstrated in either subclone. As tumors grown in nude mice derived from the sensitive and resistant clones responded equally well to an intratumoral injection of TNF, we conclude that different mechanisms are responsible for sensitivity and resistance to the cytotoxic effect of TNF in vitro and in vivo.

Animals↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

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↗