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Biomedical subjects

H Zwierzina

Publications and source records attributed to H Zwierzina.

At least 19 recordsLinked to original sources
PubMed1995

Cloning and genomic characterization of LST1: a new gene in the human TNF region.

The leucocyte specific transcript - 1 (LST1) represents the human homolog of the mouse B144 transcript, encoded within the tumor necrosis factor (TNF) region of the human major histocompatibility complex class III interval. The gene is localized about 4 kilobases upstream of the lymphotoxin beta gene. It spans a polymorphic genomic region encompassing the microsatellites TNFd and TNFe in intron 3 and a polymorphic Pvu II restriction site 260 base pairs downstream of the polyadenylation signal. Isolation of a full-length cDNA clone revealed that LST1 codes for IFN-gamma-inducible 800 nt transcripts, which are present in lymphoid tissues, T cells, macrophages, and histiocyte cell lines. The cDNA contains three long open reading frames (ORF) with the most likely ORF encoding a transmembrane protein. Its close linkage to the TNF genes and pattern of expression point toward a possible role for LST1 in the immune response.

Amino Acid Sequence↗
PubMed1992

A randomized phase-I/II multicenter study of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for patients with myelodysplastic syndromes and a relatively low risk of acute leukemia. EORTC Leukemia Cooperative Group.

To assess the effects of GM-CSF in patients with myelodysplasia, a total of 101 patients with refractory anemia (RA), RA with ringed sideroblasts (RARS), and RA with an excess of blasts provided that the percentage of blasts in the bone marrow did not exceed 10% (RAEB) were enrolled in the EORTC Leukemia Cooperative Group study 06885. They were randomized to receive two daily subcutaneous injections of rhGM-CSF (mammalian, glycosylated, Sandoz/Schering-Plough) at a daily dose of either 108 micrograms glycoprotein (group I) or 216 micrograms glycoprotein (group II) for 8 weeks. Response was defined as an increase in Hb (greater than 2.5 g%), neutrophil count (more than 100%), or platelet count (more than 100%) without progression of the disease. After exclusion of 19 patients who did not meet the entry criteria, 82 were evaluated. Fifty-four patients (66%) responded (27 of 42 patients in group I and 27 of 40 in group II). Progressive disease was seen in two patients of group I and in four of group II. Two of the latter developed leukemia. All responses were reflected in the granulocytic series. In two patients platelet numbers also increased. Cytogenetic analysis, successfully performed in 43 cases, showed that 14 of 16 patients with normal karyotypes responded, compared with 14 of 27 patients with abnormal karyotypes (p = 0.008). In some cases GM-CSF was reduced in dose or discontinued prematurely due to side effects so that only 35% of all evaluable patients finished 8 weeks of treatment without a change of dose.

Acute Disease↗
PubMed1992

Treatment of myelodysplastic syndromes (MDS) and high leukaemic risk with low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rh GM-CSF). The EORTC Leukaemia Group.

Symptomatic patients with myelodysplastic syndromes (MDS) and 10-30% blasts in the bone marrow were treated with low-dose AraC (2 x 10 mg/m2 subcutaneously (sc) days 1-14) and GM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day sc) given either subsequently (days 15-21) or simultaneously (days 8-14 and one week rest). Evaluations were carried out after three courses (nine weeks); responding patients could be continued for two further cycles. Eighty-two patients with refractory anaemia and excess of blasts (RAEB), with (RAEBt) or without transformation, were evaluable: 45 RAEB and 37 RAEBt, mean age 64 years (range 17-80 years). A complete remission was achieved in 14 cases (17%), 11 had a good response (13%), and 12 a partial response (15%). Stable disease was found in 21 cases (26%). There were 12 cases of toxic death (15%), progression was noted in eight patients (10%), and death due to disease in three (4%). No difference existed between the two treatment arms with respect to response. Major adverse events during treatment were haemorrhage (25%), infections (23%), and fever with GM-CSF (21%). GM-CSF did not induce leukaemia nor contribute to haemorrhage induced by AraC, but gave rise to an overall response rate of 46% which is high and relatively durable as compared to other treatments in this disease.

Acute Disease↗
PubMed1992

Endogenous serum levels and surface receptor expression of GM-CSF and IL-3 in patients with myelodysplastic syndromes.

The majority of patients suffering from myelodysplastic syndromes (MDS) die of complications due to cytopenia. Clinical trials have demonstrated that in an essential number of MDS patients cytopenia can be ameliorated by exogenously supplied growth factors. We investigated endogenous serum levels of GM-CSF and IL-3 in 15 healthy individuals and 34 patients suffering from MDS. No circulating growth factors were detected in the serum of healthy controls, nor was IL-3 measurable in MDS patients. GM-CSF serum levels, however, were elevated in a significant number of patients (26.5%). Levels did not correlate with FAB classification, leukocyte count or chromosomal abnormalities. No significant differences in GM-CSF or IL-3 receptor expression were detected between healthy individuals and MDS patients. One patient with increased endogenous GM-CSF serum level and normal surface receptor expression responded to exogenously applied GM-CSF. In the light of these results, a functional alteration of growth factor receptors or disturbances of signal transduction pathways must be discussed for MDS.

Adult↗
PubMed1992

Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report.

BACKGROUND: Granulocytopenia and agranulocytosis are severe side effects of clozapine therapy. Even if these side effects are detected early and if clozapine is discontinued, patients suffering from agranulocytosis are extremely endangered by infectious diseases for up to 3 to 4 weeks until hematologic recovery. Therefore, any treatment that reduces this critical time span would decrease the risks of clozapine treatment. METHOD: The case of a patient in whom severe agranulocytosis developed after 7 weeks of clozapine treatment is presented. RESULTS: After clozapine discontinuation, treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein that has been shown to stimulate the proliferation of precursor cells in the bone marrow and their differentiation into granulocytes and macrophages, was initiated. Under GM-CSF treatment, total granulocyte count rose from 63/cu mm to a value greater than 1500/cu mm within 5 days without complications or major side effects. CONCLUSION: This case report suggests that treatment with GM-CSF may lower the risks associated with clozapine-induced agranulocytosis and therefore may indirectly improve the safety of clozapine therapy.

Adult↗
PubMed1991

Epidermal Langerhans cells in myelodysplastic syndromes are abnormal.

The myelodysplastic syndromes (MDS) represent clonal disorders of the hematopoietic stem cell that are associated with quantitative and qualitative disturbances of the peripheral blood cells and a high risk for the transition to overt leukemia. As epidermal Langerhans cells (LC) are bone-marrow-derived cells, we were interested to see whether they are altered in patients with MDS. Epidermal sheets were prepared from biopsies taken from the thighs of nine patients with MDS and five control persons and processed for immunoperoxidase staining of CD1a antigens. The density and morphology of CD1a+ cells (i.e., LC) was evaluated by visual assessment as well as automatic image analysis. The density of LC was reduced in seven of nine patients (range, 30-75% of normal), whereas the morphology of LC appeared to be altered in all MDS patients in that the LC displayed large and bizarre cell bodies with only a few and often abnormally long dendrites. The HLA-DR expression by LC was not altered, as shown by double immunofluorescence staining of CD1a and HLA-DR antigens. Ultrastructurally, LC again appeared enlarged and often presented with bizarre nuclei, yet displayed no other abnormalities. Our findings suggest that LC are abnormal in MDS and might even indicate a more wide-spread involvement of the dendritic cell lineage in this syndrome.

Humans↗
PubMed1991

Detection of soluble IL-2 receptor in the serum of patients with myelodysplastic syndromes: induction under therapy with GM-CSF.

Sera of 15 healthy controls and 33 patients suffering from myelodysplastic syndromes (MDS) were investigated for soluble interleukin-2 receptor (sIL-2R) expression with a cell-free enzyme-linked immunosorbent assay (ELISA) system (T-Cell Sciences; Cambridge, U.S.A.). The upper limit of the assay is indicated with 477 U/ml. According to the FAB classification eight refractory anaemia (RA), 15 refractory anaemia with excess of blasts (RAEB), five refractory anaemia with excess blasts in transformation (RAEBt) and five chronic myelomonocytic leukaemia (CMML) were examined. None of the patients had reported infectious episodes or been under treatment with cytotoxic agents and/or cytokines within the previous 3 months. Significant differences in sIL-2R levels between RA (median 368 U/ml). RAEB (median 675 U/ml) and RAEBt (median 971 U/ml) and between RA and CMML (median 723 U/ml) were detected. Six patients, who had been under treatment with rhGM-CSF for at least 2 weeks, demonstrated a three- to sevenfold increase of sIL-2R expression compared to pretreatment levels. In kinetic evaluation of serum samples for 24 h, the increase of sIL-2R expression begins within 4 h after subcutaneous application of GM-CSF and reaches its maximum after 12 h. Our data cannot suggest whether increased sIL-2R expression is a primary event due to involvement of lymphocytes in the malignant clone or whether it results from secondary alteration of the cytokine network. Application of GM-CSF in MDS may result in improvement of altered lymphocyte function. As GM-CSF induces sIL-2R expression, a down regulation of the immune response caused by neutralization of free IL-2 cannot be excluded.

Adult↗
PubMed1991

[In vitro effects and possible clinical relevance of interleukin 3].

Cytokines are mainly produced by monocytes and lymphocytes and influence a broad spectrum of physiological processes within the hematopoietic and the immune system. Clinical trials have mainly been initiated with a subgroup of cytokines namely the hematopoietic growth factors. Interleukin 3 (IL-3) was recently introduced into phase I and II trials. This factor was also termed "multipoietin" because of its ability to stimulate in vitro the hematopoietic stem cell and thus all three hematopoietic cell lines. The latest in vivo data, however, demonstrate that IL-3 stimulates leukopoiesis and megakaryopoieis with only marginal effects on erythropoiesis. In large clinical trials the therapeutic effect of this factor is investigated in patients with myelodysplastic syndromes. Further indications will be other primary bone marrow failures and aplasia caused by bone marrow transplantation, aggressive chemotherapy and radiation. Potential applications offered by combinations with other cytokines can hardly be foreseen.

Animals↗
PubMed1991

[Hematopoietic growth factors].

Hematopoietic growth factors represent a subgroup of the cytokines and are also called colony-stimulating factors (CSFs) because of their effects in bone marrow culture. These glycoproteins are produced by a large number of cells and serve to transmit signals within the hematopoietic and the immune system either by themselves or by inducing the production and the release of other cytokines. As their genes have been cloned by molecular biology in the last year, these "recombinant" factors can be produced in large amounts for clinical trials. Cytokines make possible completely new therapy concepts by enabling medicine both to intervene in and modulate the body's own physiological processes. Therapy studies conducted with hematopoietic growth factors to date are encouraging and mostly demonstrate only tolerable dose-dependent side effects. In contrast to the maximal tolerable dose usually applied for cytotoxic therapy regimens, this "biological therapy" aims to a minimal effective dose, known e.g. from interferon. The following article will attempt to provide an insight into the first results of clinical trials and in future possibilities in the clinical application of these factors.

Animals↗
PubMed1990

Stimulation of colony formation of various human carcinoma cell lines by rhGM-CSF and rhIL-3.

We studied the effects human recombinant granulocyte-macrophage colony-stimulating factor and human recombinant interleukin-3 on the colony formation of three human solid tumor cell lines. Using a modified double-layer soft agar clonogenic assay rhGM-CSF enhanced colony formation of all cell lines tested in a dose dependent manner (up to twofold for the breast cancer cell line BT-20, up to 163% of the control for the hypernephroma cell line C 94 and up to 147% for the non-small cell lung cancer cell line CCL 185 at a concentration of 100 ng/ml). RhIL-3 stimulated colony formation of the cell lines C 94 and BT-20, whereas on the cell line CCL 185 rhIL-3 had no effect even at the highest dose level tested (100 ng/ml). Combinations of growth factors showed subadditive stimulation on two cell lines tested (BT-20, C 94). These data indicate that haematopoietic growth factors exert a growth promoting activity on certain solid tumor cells in vitro at physiological concentrations. Therefore our results suggest that the application of these factors in immuno- and myelosuppressed cancer patients after high dose chemotherapy should be seen in light of a possible co-stimulation of the malignant cells.

Agar↗
PubMed1989

Delayed maturation of skin window macrophages in myelodysplastic syndromes.

Blood monocyte differentiation to macrophages was examined in nine patients with primary myelodysplastic syndromes using the skin window technique. Emigrated cells were stained cytochemically for acid phosphatase reaction after 1, 2, 4, 7, 9, 12 and 23 h. Compared to age-matched controls, seven patients showed a significant delay in lysosomal enzyme acquisition, which is associated with macrophage differentiation. Our results with this in-vivo assay demonstrate an involvement of the monocyte/macrophage system in primary myelodysplastic syndromes and show that patients often have a disturbance in macrophage differentiation.

Acid Phosphatase↗
PubMed1989

Abnormal megakaryopoiesis in patients with myelodysplastic syndromes: analysis of cellular and humoral defects.

In 13 patients with myelodysplastic syndrome (MDS) mature and immature erythropoietic (CFU-E, BFU-E), granulopoietic (CFU-GM) and megakaryopoietic (CFU-Meg) colony formation from human bone marrow mononuclear cells was evaluated in a microagar culture system. All but three patients exhibited abnormal CFU-Meg. The defect of CFU-Meg paralleled the reduction of BFU-E, whereas CFU-GM number declined to a lesser extent. Not only the CFU-Meg number, but also the number of megakaryocytes (Mk) per colony was reduced suggesting an additional functional CFU-Meg defect. Megakaryocytic growth factor (Meg-CSF) abnormalities in MDS patients were detected using normal nonadherent T-lymphocyte depleted bone marrow cells as target cells for serum testing. Even for sera from patients with a reduction of platelets and bone marrow megakaryocytes Meg-CSF levels were not increased. No cellular or humoral inhibition could be detected in an MDS patient with a 5q- karyotype, who had an isolated defect of the megakaryocytic cell lineage at presentation. Some patients revealed a spontaneous formation of mixed erythrocytic, granulocytic and megakaryocytic clusters in the presence of fetal calf serum or autologous patient serum, probably representing autonomous proliferation of the malignant clone. In conclusion, both cellular and humoral factors can cause abnormalities of the megakaryocytic cell lineage in MDS patients.

Adult↗