Interleukin 1 induces different cytokines in human fibroblasts.
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Biological Factors↗
Biomedical subjects
W E Fibbe
Publications and source records attributed to W E Fibbe.
Haematopoietic growth factors.
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Colony-Stimulating Factors↗
Comparison of intensive consolidation therapy and autologous bone marrow transplantation in acute myeloid leukaemia. The Leiden experience.
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Adolescent↗
A single low dose of human recombinant interleukin 1 accelerates the recovery of neutrophils in mice with cyclophosphamide-induced neutropenia.
The actions of the cytokine interleukin 1 (IL-1) in hematopoiesis involve induction of colony-stimulating factor (CSF) production on accessory cells in the hematopoietic microenvironment and synergy with CSF on early hematopoietic progenitor cells. We have used these properties to accelerate hematologic reconstitution in granulocytopenic mice. Mice with cyclophosphamide-induced granulocytopenia were injected i.p. at day 0 with a single dose (8-800 ng) of human recombinant IL-1 alpha. At daily intervals thereafter during a period of 7 days mice were sacrificed and blood granulocytes and bone marrow cellularity were assessed. Mice receiving a single dose of 80 or 800 ng IL-1 had significantly (p less than 0.05) higher blood granulocyte counts at days 4 and 5 than control animals receiving heat-activated IL-1. This activity of IL-1 was not affected by injection of the cyclooxygenase inhibitor ibuprofen. Bone marrow cellularity, as assessed in histological sections of femurs, was significantly greater (p less than 0.05) at day 2 in mice treated with 80 or 800 ng IL-1. These results show that a single low dose of IL-1 may be used to accelerate the reconstitution of granulocytes following granulocytopenia induced with chemotherapy.
Agranulocytosis↗
Cellularly defined minor histocompatibility antigens are differentially expressed on human hematopoietic progenitor cells.
Previously, five CTL lines directed against minor histocompatibility (mH) antigens designated HA-1-5 have been established from peripheral blood of patients after allogeneic bone marrow transplantation (BMT), and have been characterized using population and family studies. All cell lines showed specific HLA class I-restricted lysis of PHA-stimulated peripheral blood target cells from donors positive for the particular mH antigens. After 4 h of incubation of the mH antigen HA-3-specific CTL line with bone marrow cells from HA-3+ donors, complete class I-restricted inhibition of colony growth of the hematopoietic progenitor cells was observed even at low E/T ratios, indicating that the HA-3 antigen is strongly expressed on hematopoietic stem cells. Therefore, this antigen may be a target structure in the immune-mediated rejection of the hematopoietic graft in case of incompatibility for this determinant between donor and recipient in allogeneic BMT. In contrast, incubation of bone marrow cells with the antigen-specific anti-HA-1, -2, -4, and -5 CTL lines did not result in growth inhibition of the hematopoietic progenitor cells tested. After a prolonged incubation time and using a very high E/T ratio, progenitor cells from HA-2+ or HA-5+ donors were killed to some extent by the anti-mH-specific CTL lines, although the growth inhibition observed was minor and variable. Our results show that mH antigens are differentially expressed on human hematopoietic progenitor cells. Therefore, only some of these antigens may be targets in immune-mediated rejection of the bone marrow graft.
Cell Line↗
Neutropenia and infections in Felty's syndrome.
Fifteen patients with Felty's syndrome (FS) were studied prospectively during a 3-year period to determine the influence of multiple haematologic parameters on the incidence of infections. An increased risk of recurrent major and minor infections was primarily related to peripheral blood polymorphonuclear cell (PMN) counts of less than 0.1 x 10(9)/l. Bone marrow lymphocytosis, a decreased percentage of PMN in bone marrow differential counts and an impaired in vitro growth of colony-forming unit-PMN macrophage were also related to an increased incidence of infection but were predominantly present in patients with less than 0.1 x 10(9)/l circulating PMN. The maximal response in the number of circulating PMN measured after injection of epinephrine and hydrocortisone varied substantially within patients, but those with less than 0.1 x 10(9)/l PMN always had lower responses than those with greater than 0.1 x 10(9)/l PMN. These variables did not therefore contribute to the identification of FS patients at risk of infection.
Agranulocytosis↗
Factors influencing release of granulocyte-macrophage colony-stimulating activity from human mononuclear phagocytes.
Mononuclear phagocytes play an important role in the regulation of hematopoiesis, not only by producing regulatory monokines such as prostaglandins, tumor necrosis factor and interleukin-1 (IL-1), but also by the production of colony-stimulating activity (CSA). Previously, we have demonstrated that granulocyte-macrophage CSA (GM-CSA) production by mononuclear phagocytes can be induced by IL-1. In the present study, the influence of culture conditions on the production of GM-CSA was studied. It was found that both human sera and fetal bovine sera contain constituents - at present undefined - that induce GM-CSA production. These factors are distinct from IL-1 and lipopolysaccharide. In selected experiments, no GM-CSA-inducing effect of serum was found, suggesting that the effect may be donor-related. GM-CSA release in the presence of serum could be reduced by 40% after incubation of mononuclear phagocytes at low cell concentrations in methylcellulose, indicating that intimate cell-cell contact is an additional factor that enhances GM-CSA release.
Animals↗
Minor histocompatibility antigen H-Y is expressed on human hematopoietic progenitor cells.
Polymorphic minor transplantation antigens probably play an important role in immune mediated graft rejections of bone marrow transplants. Mapping of these antigens on hematopoietic progenitor cells (HPC) is important since these antigenic determinants may serve as target structures in the rejection process, and it ultimately opens the possibility to match for these antigens. Using a cell-mediated cytotoxicity assay with H-Y-specific cytotoxic T lymphocytes as effector cells, a dose-dependent growth inhibition up to 100% of myeloid (CFU-GM), erythroid (BFU-E) and multipotential (CFU-GEMM) HPC of male donors was obtained, indicating expression of the H-Y antigen on these progenitor cells. In contrast, inhibition of relatively mature erythroid and myeloid progenitor cells was only 40-50%, indicating that the recognition of the H-Y antigen diminished during maturation of erythroid and myeloid HPC. Our results show that the H-Y antigen can be recognized on HPC as a target for cytotoxic T cell responses. This may be important in graft rejection of male donor bone marrow grafts by female recipients.
Bone Marrow↗
Interleukin 1 induces human marrow stromal cells in long-term culture to produce granulocyte colony-stimulating factor and macrophage colony-stimulating factor.
Pure interleukin 1 (IL 1) was found to stimulate established human bone marrow stromal layers in long-term culture to produce colony-stimulating activity (CSA). Maximal concentrations in the culture medium were reached 24 hours after a single IL 1 pulse. The effect could be neutralized by a specific rabbit anti-IL 1 antiserum. Stromal layers, once stimulated by IL 1, continued to release CSA into the culture medium in the absence of exogenous IL 1. A second IL 1 pulse induced CSA release in an identical manner, as did the primary stimulation, indicating that the CSA released was actively produced. Using specific immunologic assays, both granulocyte colony-stimulating factor (G-CSF) and macrophage CSF (M-CSF) could be identified in the culture supernatants, and production of both factors was inducible by IL 1. Shortly after initiation of the long-term marrow cultures "spontaneous" G-CSF and M-CSF release occurred. The release of G-CSF diminished following addition of the anti-IL 1 antiserum, indicating that endogenous production of IL 1 by stromal cells had contributed to this effect. These results further support the role of IL 1 as an important modulator of CSF production by cells of the hematopoietic microenvironment.
Bone Marrow↗
Human fibroblasts produce granulocyte-CSF, macrophage-CSF, and granulocyte-macrophage-CSF following stimulation by interleukin-1 and poly(rI).poly(rC).
Electrophoretically pure human interleukin-1 (IL-1) beta was found to stimulate human fibroblasts in a monolayer culture to elaborate colony-stimulating activity (CSA). Supernatant fluids from cultures induced with increasing concentrations of IL-1 were found to stimulate colony formation of myeloid (CFU-GM), erythroid (BFU-E), and multipotent (CFU-GEMM) progenitor cells in a dose-dependent fashion. The effect on mixed colony formation, however, was less than on CFU-GM and BFU-E growth. Similar to IL-1, the synthetical double-stranded RNA poly(rI).poly(rC) also stimulated release of CSA by fibroblasts. The kinetics of IL-1- and poly(rI).poly(rC)-induced CSA release were found to be different, in that poly(rI).poly(rC)-induced CSA production occurred more slowly. Anti-IL-1 antiserum was able to completely neutralize the IL-1-induced CSA release, but had no effect on poly(rI).poly(rC)-induced CSF production, suggesting that the latter effect was mediated by other mechanisms than IL-1 in supernatant. By the use of specific immunologic assays, G-CSF, M-CSF, and GM-CSF could be identified in media conditioned by fibroblasts treated with IL-1 or poly(rI).poly(rC). Poly(rI).poly(rC) appeared to be a better inducer for M-CSF than IL-1.
Colony-Forming Units Assay↗
Proliferation of myeloid progenitor cells in human long-term bone marrow cultures is stimulated by interleukin-1 beta.
To study the effect of interleukin-1 (IL-1) beta on the proliferation of hematopoietic progenitor cells (HPC) in long-term bone marrow cultures (LTBMC), stromal cell layers were established from normal human bone marrow. Autologous cryopreserved mononuclear phagocyte- and T-lymphocyte-depleted bone marrow cells were reinoculated on the stromal layers in fresh culture medium, with or without the addition of human IL-1 beta (30 U/mL). Once a week, half of the culture supernatant was replaced with fresh culture medium with or without IL-1, and all nonadherent cells were returned to the flasks. At weekly intervals during a period of 5 weeks, one culture was sacrificed to determine the total number of cells and hematopoietic progenitor cells, present in the adherent and the nonadherent cell fractions. In IL-1-stimulated cultures, the number of cells recovered during a period of 5 weeks exceeded the number of cells in unstimulated control cultures by 1.5 times. This difference was attributed to a twofold increase in the number of adherent cells. The number of HPC recovered from IL-1-stimulated cultures was not different from that recovered from controls. The levels of colony-stimulating activity (CSA) in supernatants from IL-1-stimulated cultures were significantly higher than those in supernatants from control cultures. These results indicate that IL-1 enhances the recovery of cells in LTBMC by stimulating the proliferation of HPC with the concurrent release of CSA from stromal cells, without diminishing the number of HPC.
Bone Marrow Cells↗
Hairy cell leukemia: in-vitro proliferation and pseudo-colony formation.
In an established double layer clonogenic assay, the PHA-leukocyte feeder colony assay, hairy cell leukemia (HCL) cells formed strong aggregates simulating colonies. After irradiation with 50 Gy, colony formation persisted. Even in a modified colony assay consisting of agar 0.5% overlayered by methylcellulose 0.9%, cell aggregation was still possible due to increasing fluidity of the methylcellulose during the culture period. Time-lapse video recordings confirmed prominent cell motility leading to pseudo-colony formation. Studies with bromodeoxyuridine incorporation showed a low proliferation index (up to 13%) of hairy cells. In conclusion, any assay that facilitates cell motility is unsuitable to study HCL colony growth.
Bromodeoxyuridine↗
B-cell colony growth of malignant and normal B-cells.
B-cell colony growth of malignant and normal B-cells has been studied in a double layer (agar-fluid) colony assay. Stimulatory factors consisted of irradiated blood leukocytes, phytohaemagglutinin (PHA), interleukin 2 (IL2) and 12-0-tetradecanoylphorbol-13-acetate (TPA) in various combinations. B-cell colonies have been obtained in all cases tested, i.e., 7/7 cases with chronic lymphocytic leukaemia, 7/7 cases with non-Hodgkin's lymphoma, 5/5 cases with hairy cell leukaemia and 7/7 normal B-cell suspensions, obtained from blood (X 3), bone marrow (X 2) and spleen (X 2). The plating efficacy ranged from 0.02-0.35, with a median of 0.07. Colony formation was found to be linear (r = 0.96) in the plating range of 0.5-8 X 10(5) cells. Secondary colonies could be obtained in 2 cases tested. DNA synthesizing cells in colonies were determined in 4 cases using monoclonal antibodies against DNA-incorporated bromodeoxyuridine (BrdUrd). In most cases the combination of PHA (with or without IL2) and irradiated leukocytes yielded the highest number of colonies, but in some experiments stimulation with TPA + IL2 was found to be optimal.
B-Lymphocytes↗
Cell-mediated lysis of human hematopoietic progenitor cells.
Several techniques are available for the serological analysis of antigenic determinants on human hematopoietic progenitor cells (HPC). However, techniques for the recognition of cellularly defined antigens on such progenitor cells have not yet been described. We therefore developed an in vitro cellular cytotoxicity assay, with bone marrow cells as target cells. In this assay specific cytotoxic T lymphocyte (CTL) lines are used as effectors for cell-mediated cytolysis of bone marrow mononuclear cells that express the antigens for which the CTLs were primed in a mixed lymphocyte culture. As a model we used CTL lines against HLA-A2 or -B7 determinants. By using effector-target ratios varying from 1:2 to 4:1, 4 hr of incubation of these CTL lines with bone marrow mononuclear cells from HLA-A2 or -B7 positive donors resulted in a specific dose-dependent growth inhibition up to 100% of myeloid (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) HPC. In contrast no inhibition of HPC was observed using mononuclear bone marrow cells from HLA-A2 or -B7 negative individuals as target cells. Experiments in which cell-cell contact was prevented showed that the antigen-specific lysis of HPC was dependent on intimate cell-cell contact between effector-CTLs and bone marrow target cells. Our results show that this cell-mediated cytotoxicity assay can be used as a sensitive and specific tool for the study of cellularly defined antigens on human hematopoietic progenitor cells.
Antigens, Surface↗
Factors influencing the incidence of infections in Felty's syndrome.
To identify clinical and laboratory risk factors for the susceptibility to infections in Felty's syndrome, 46 patients were studied prospectively during a total number of 431 periods of three months ("patient-quarters"). The incidence of infections increased significantly with polymorphonuclear leukocyte (PMN) counts below 0.1 X 10(3)/mm3 (less than 0.1 X 10(9)/L). At PMN levels over 0.1 X 10(3)/mm3 (greater than 0.1 X 10(9)/L), no association was found between PMN counts and the incidence of infections. Other factors found to be associated with an increased incidence of infections were severe disability, skin ulcers, glucocorticosteroid dose, monocyte counts, hypocomplementemia, and high levels of circulating immune complexes. The activity of the rheumatoid arthritis, erythrocyte sedimentation rate, hemoglobin concentrations, and lymphocyte counts were not associated with increased incidence of infections.
Arthritis, Rheumatoid↗
Interleukin 1 as a cytokine inducer.
Human interleukin 1 (IL 1) exerts an interferon-like antiviral activity in certain strains of human diploid fibroblasts. It is shown that this antiviral effect is indirect, in that it is mediated by production of interferon-beta. IL 1 also induces synthesis of the mRNA of another secreted protein, 26K, whose biological function is still controversial. Finally, IL 1 has bone marrow colony stimulating activity which is shown to be due to induction of colony stimulating factor in adherent phagocytic cells present in the bone marrow cultures. These findings emphasize the concept that several of the varied biological effects of IL 1 may be indirect.
Bone Marrow Cells↗
Agranulocytosis induced by propylthiouracil: evidence of a drug dependent antibody reacting with granulocytes, monocytes and haematopoietic progenitor cells.
A patient with agranulocytosis and myeloid marrow hypoplasia following a second exposure to propylthiouracil (PTU) was studied for antibodies against mature blood cells and bone marrow precursor cells. During the acute phase of the agranulocytosis, significant growth inhibition of the myeloid committed progenitor cells (CFU-GM) was found following incubation with complement, indicating the presence of in-vivo cell bound cytotoxic antibodies. Using immunofluorescence and complement dependent cytotoxicity techniques it was demonstrated that acute phase and recovery phase sera contained circulating antibodies, reactive not only with differentiated granulocytes and monocytes but also with myeloid and erythroid (BFU-E/CFU-E) progenitor cells. Complement dependent lysis of the progenitor cells was facilitated by preincubation with PTU. These results indicate that the agranulocytosis was mediated by a PTU dependent antibody that affected both mature blood cells and bone precursor cells.
Aged↗
Selective removal of clonogenic neoplastic B cells from human bone marrow using anti-HLA-DQ antibodies and complement.
Polymorphic HLA-DQ (DC/MB) determinants appeared to be not expressed on human hematopoietic progenitor cells (HPC), using several murine monoclonal and human polyclonal antibodies in a complement-dependent cytotoxicity (CDC) assay. Since mature HLA-DR-positive malignant lymphoma cells prove to be HLA-DQ positive, an attempt was made to remove clonogenic neoplastic DQwl-positive B cells selectively from DQwl-positive marrow samples without affecting hematopoietic progenitor cells. Using a combination of a clonogenic tumor cell assay, an HPC culture assay, and a mixed-tumor-cell-HPC culture assay, selective elimination of more than 98% of clonogenic neoplastic cells from tumor-cell-contaminated bone marrow suspensions was achieved with monoclonal anti-DQ antibodies and complement without depletion of HPC. These results indicate that anti-HLA-DQ antibodies can be used in autologous bone marrow transplantation to deplete the bone marrow cell suspension of DQ-positive malignant cells.
Antibodies, Monoclonal↗