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PubMedDate not supplied

Studies on nude mice bearing human CSF-producing tumor. III. Colony type of granulocyte-macrophage precursors of nude mice bearing CSF-producing tumor.

In previous studies, we analyzed the hemopoietic precursor cells of tumor-bearing nude mice with marked neutrophilia induced by a transplanted human lung cancer. In this study, we examined the morphology of granulocyte-macrophage colonies using a technique for cytochemical examination of all colonies grown in agar gel culture. By stimulation with spleen cell-conditioned medium, the bone marrow cells and spleen cells of tumor-bearing nude mice formed a higher proportion of granulocyte-containing colonies than those of control mice. However, a larger number of granulocyte-macrophage progenitors were not definitely committed to differentiate into granulocytes and macrophages, as no significant differences in cellular composition of colonies between tumor-bearing mice and control mice were observed by stimulation with L cell-conditioned medium.

Animals↗

PubMed1993

Analysis of myeloid characteristics in acute lymphoblastic leukemia.

We examined myeloid characteristics of myeloid-antigen-positive (My+) and -negative (My-) B-precursor acute lymphoblastic leukemia (ALL) blast cells. Immunophenotyping before and after culture, rearrangements of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) genes, stimulation of DNA synthesis with granulocyte colony-stimulating factor (G-CSF), and G-CSF binding assay were performed. Of My+ ALL blasts, the immunophenotypic staging as B-precursor ALL and rearrangements of IgH and TCR-beta, gamma and delta genes did not differ from findings in My- ALL blasts. Stimulated with G-CSF, cells from one My+ ALL and from one My- ALL patients showed enhancement of DNA synthesis and expression of CD11b and CD13, respectively. G-CSF binding was observed in blasts from 3 My+ ALL patients and one My- ALL child. After culture, blasts from My- ALL children expressed CD13 but showed neither enhanced DNA synthesis with G-CSF nor G-CSF binding. Thus, it would appear that (i) My+ and My- adult ALL blasts are at the same stage of differentiation; (ii) some My+ adult ALL blasts have phenotypic and functional myeloid characteristics; and (iii) induction of CD13 expression in My- ALL after in vitro culture does not correlate with other myeloid characteristics.

Adolescent↗

PubMed1999

Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.

OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.

Animals↗

PubMed1992

Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.

Antigen-presenting, major histocompatibility complex (MHC) class II-rich dendritic cells are known to arise from bone marrow. However, marrow lacks mature dendritic cells, and substantial numbers of proliferating less-mature cells have yet to be identified. The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II-negative precursors in marrow. A key step is to remove the majority of nonadherent, newly formed granulocytes by gentle washes during the first 2-4 d of culture. This leaves behind proliferating clusters that are loosely attached to a more firmly adherent "stroma." At days 4-6 the clusters can be dislodged, isolated by 1-g sedimentation, and upon reculture, large numbers of dendritic cells are released. The latter are readily identified on the basis of their distinct cell shape, ultrastructure, and repertoire of antigens, as detected with a panel of monoclonal antibodies. The dendritic cells express high levels of MHC class II products and act as powerful accessory cells for initiating the mixed leukocyte reaction. Neither the clusters nor mature dendritic cells are generated if macrophage colony-stimulating factor rather than granulocyte/macrophage colony-stimulating factor (GM-CSF) is applied. Therefore, GM-CSF generates all three lineages of myeloid cells (granulocytes, macrophages, and dendritic cells). Since > 5 x 10(6) dendritic cells develop in 1 wk from precursors within the large hind limb bones of a single animal, marrow progenitors can act as a major source of dendritic cells. This feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.

Animals↗

PubMed1996

Persistence of mixed chimerism in patients transplanted for the treatment of thalassemia.

Molecular genetic techniques permit sensitive assessment of host hematopoiesis after marrow transplantation for thalassemia. Information on this persistence and the cell lines in which it occurs may permit therapeutic intervention in patients at high risk for rejection and/or relapse. The objective of this study, therefore, was to determine the evolution and cell line distribution of persistent mixed chimerism detected in 55 patients treated for beta thalassemia. Our findings indicated that rejection occurred in 20 patients, the host component disappeared in 20, and mixed chimerism without transfusion need persisted for 1 to 7 years in 15. In three patients with stable mixed chimerism for 4, 5, and 7 years, host hematopoiesis fluctuated between 25% and 75%. Despite this, donor pattern beta-globin chain synthesis maintained hemoglobin levels between 10 and 13.5 g/dL without transfusion. In these three patients, the polymerase chain reaction of the VNTR and the fluorescent in situ hybridization analysis revealed the coexistence of donor and host cells in the different peripheral blood cell subpopulations and precursors studied (CD2+, CD4+, CD8+, and CD19+ granulocytes; glycophorin-A+, erythroid burst-forming units, CD33+, granulocyte-macrophage colony-forming units). We found that rejection and disease recurrence occur in approximately one third of patients with early mixed chimerism. High levels of host type hematopoiesis can be present in patients not requiring transfusion.

Adolescent↗

PubMed1993

5-fluorouracil and mast cell precursors in mice.

In the mouse hematopoietic system, 5-fluorouracil (5-FU) reversibly inhibits the generation of multilineage colonies containing granulocyte, erythroid, megakaryocyte, and macrophage lineage. To determine the effect of 5-FU on mastopoiesis in vitro, bone marrow cells were obtained from mice, cultured, and treated with 5-FU for 14 days in an interleukin-3 (IL-3)-enriched medium. A dose-related inhibitory effect of 5-FU on mastopoiesis was found. When an inhibitory dose (1 microgram/mL) of 5-FU was supplemented to the cultures for only 2, 4, or 8 days and the cells were then recultured without the drug, we observed inhibition of mastopoiesis directly related to the time of exposure of the cells to 5-FU. To determine the effect of 5-FU on mastopoiesis in vivo, bone marrow cells from mice that had received a single intravenous (i.v.) 5-FU injection (150 mg/kg) were cultured. A virtually total absence of mast cells was noted at days 1 and 2 following 5-FU administration. A gradual reappearance of mast cells was later observed. Whether mice were injected with the drug once or with four once-daily (100 mg/kg 5-FU) injections, a similar pattern of delay of mast cell appearance was observed. The findings suggest (1) an irreversible, nonadditive, toxic effect of 5-FU on mast cell precursors and (2) that most or all of the mast cell precursors are nonquiescent cells, continuously activated or cycling. In addition, the use of 5-FU may serve as a unique model system for controlling and studying mastopoiesis in normal mice, rather than the mutated mice currently studied.

Animals↗

PubMed1980

Haematopoietic growth factors are released in cultures of H-2-restricted helper T cells, accessory cells and specific antigen.

Colony formation by mammalian haematopoietic cells in culture depends on specific glycoprotein growth factors. 'Colony-stimulating factors' for granulocytic and macrophage precursors (G- and M-CSFs), as well as for pluripotential and early committed erythroid cells ('burst promoting activity, or BPA) are released in cultures of stimulated spleen, lymph node or peripheral blood cells. In such systems the induction stimulus has been either allogenic cell antigens, or lectins which stimulate T cells, such as pokeweed mitogen, concanavalin A (Con A) or phytohaemagglutin and both T cells and adherent cells are implicated in the process. The complexity of the spleen cell populations used in earlier in vitro studies has made it difficult to establish the cellular source of the factors and the mechanisms leading to their release. Pure populations of continuously growing cell lines of either monocytic/macrophage or T-cell character have already been shown to release haematopoietic activities constitutively. However, such evidence cannot prove that these functions are also expressed by the normal counterparts of these lines. We have reduced the complexity of the spleen cell system by supplying helper T cells in the form of pure clonal populations of known physiological function and antigenic specificity, and demonstrate here that activity is released when helper T cells are cultured with specific antigen, and that release depends on H-2 (I-A region) restricted interaction with accesory cells present in spleen or normal peritoneal cavity.

Animals↗

PubMed1986

Expression of CD11, CDw15, and transferrin receptor antigens on human hematopoietic progenitor cells.

The expression of transferrin receptor-associated antigens and of CD11 and CDw15 antigens was investigated on myeloid committed progenitor cells (CFU-GM day 10, CFU-GM day 7, and cluster-forming cells [CFC] day 4), on erythroid committed progenitor cells (BFU-E and CFU-E), and on multilineage progenitor cells (CFU-GEMM). Both complement-dependent cytotoxicity and fluorescence-activated cell-sorting assays were performed. Complement-dependent cytotoxicity appeared to be the more sensitive assay. Transferrin receptor-associated antigens appeared to be clearly present on all myeloid and erythroid committed progenitor cells, but were found to be only weakly expressed on CFU-GEMM. CD11 antigens appeared to be strongly expressed only on mature granulocytes, monocytes, and certain lymphocytes, but not significantly on myeloid committed precursor cells. Surprisingly, CD11 antigens were weakly, but significantly, present on CFU-E. CDw15 antigens appeared to be restricted to myeloid differentiation and were increasingly expressed from CFU-GM day 10 to CFC day 4. Thus, antitransferrin receptor, CD11, and CDw15 antibodies can be used to separate hematopoietic progenitor cells and may be useful tools in the study of hematopoietic differentiation.

Antibodies, Monoclonal↗

PubMed1975

Cytogenetic studies in myelomatosis.

Cytogenetic studies have been carried out on bone marrow aspirates from 25 patients with myelomatosis. Abnormal stem lines were present in 7 of the patients; the remainder had a diploid chromosome complement. In most patients - also in those without an abnormal clone - some metaphases had a blurred appearance similar to that seen in bone marrow aspirates from patients with acute leukaemia. In many of the chromosome preparations obtained before cytostatic therapy some metaphases with structural aberrations on the chromosomes were seen. Evidence is presented that in the patients with abnormal stem lines in the bone marrow, the chromosome abnormalities are confined to the myeloma cells and are not found in the erythrocytic or granulocytic precursors, which thus do not seem to be involved by the neoplastic process. Based on the present resuts and on a review of the relevant literature some general cytogenetic features are emphasized which may contribute to a better understainding of the disorder. Especially, it is demonstrated that in myelomatosis the cytogenetic changes are much more uniform than in other malignant disorders with the exception of chronic myeloid leukaemia.

Adult↗

PubMed1996

Alzheimer's amyloid precursor protein is expressed on the surface of hematopoietic cells upon activation.

A4-amyloid is the major component of senile plaques and neurofibrillary tangles found in the brain of patients suffering Alzheimer's disease. This 39-42 amino acid peptide is derived from a larger precursor protein (APP). Since APP gene encodes for a putative membrane protein, the study of APP expression at the cell surface may provide useful data for understanding its physiological function. In this report, we present data on APP expression, that was detected by APP specific mAbs in cells of the hematopoietic system. APP was weakly expressed on the cell surface of resting human lymphocytes and monocytes, but it could be induced to the surface of those cells upon stimulation. The cell activators capable of inducing APP membrane expression comprehended mitogenic lectins, calcium ionophores, phosphatase inhibitors, and anti mu-chain or anti-CD3 antibodies in B and T cells, respectively. Interestingly, phorbol esters were able to induce APP membrane expression in monocytic, but not in lymphoid cells. In contrast to lymphocytes and monocytes, granulocytes never expressed cell surface or cytoplasmic APP, even after the activation. The induction of membrane APP in response to lymphocyte activation signals, including antibodies to the antigen receptor of B and T cells, raises the possibility that APP might play the role of a cell surface receptor in the immune system.

Amyloid beta-Protein Precursor↗

PubMed1996

Distinct developmental patterns of short-term and long-term functioning lymphoid and myeloid precursors defined by competitive limiting dilution analysis in vivo.

Functional abilities of individual marrow precursor cells were defined by competitive limiting dilution without enrichment, tissue culture, or induced marking, manipulations that might affect cell functions. We directly measured long-term repopulating abilities in limiting doses (0.25-1.0 x 10(5)) of genetically marked congenic marrow cells. These were mixed with a standard dose of 4 or 5 x 10(5) competitor marrow cells, which contained a predictable distribution of precursor cells and allowed quantitative assays. Percentages of donor type T and B lymphocytes, granulocytes, platelets, and erythrocytes were measured in recipient blood. Applying the maximum likelihood statistic, concentrations (per 10(5)) of precursors repopulating at least one lineage were: 4.7 and 6.0 after 6 wk, 1.6 and 2.7 after 14 to 15 wk, and 1.2 and 1.9 after 30 to 32 wk; concentrations repopulating at least three lineages were 2.3 and 3.4 after 6 wk, 0.9 and 1.7 after 14 to 15 wk, and 0.9 and 1.3 after 32 wk. Almost all precursors functioning after 14 wk repopulated all lineages. At 6 wk, similar levels of donor cells were produced in recipients of both short- and long-term precursors. However, after 14 to 32 wk, contributions by short-term precursors (about two-thirds of the precursors) dropped to zero, while contributions by long-term precursors (about one-quarter of the precursors) expanded severalfold. The latter permanently repopulated all lineages after 30 to 32 wk, functioning as the most primitive stem cells (PSC) in the immune and myeloid systems. Nearly all the variance in long-term repopulated recipients was explained using the Poisson distribution to calculate donor percentages in a model where each donor and competitor PSC contributed equally.

Animals↗

PubMed2000

Features of severe periodontal disease in a teenager with Chédiak-Higashi syndrome.

BACKGROUND: Chédiak-Higashi syndrome (C-HS) is a rare congenital disease characterized by defective neutrophil function with abnormal lysosomal inclusions, neutropenia, and reduced chemotaxis. The complete syndrome includes oculocutaneous albinism with photophobia, neurologic features, recurrent infections, and enterocolitis. METHODS: A 14-year-old male C-HS patient was referred to us because of serious periodontal destruction with acute inflamed gingiva and ulcers. Clinical and biological investigations were performed, leading to the diagnosis of C-HS. RESULTS: Laboratory findings included neutropenia and hypergammaglobulinemia. Peripheral blood smears showed giant granules in neutrophils, eosinophils, and granulocytes. Bone marrow smears showed giant inclusions in leukocyte precursor cells. These granules and inclusions were characteristic of Chédiak-Higashi syndrome. Oral radiographic status showed extensive loss of alveolar bone leading, in most cases, to tooth exfoliation. Bacteria often associated with periodontitis were detected in subgingival plaque samples, including Fusobacterium nucleatum, Campylobacter rectus, Prevotella melaninogenica, Peptostreptococcus anaerobius, and Clostridium sp. Biopsies of periodontal tissues for light and electronic microscopic examinations revealed massive bacterial invasion of the epithelial tissue, epithelial cells, and connective tissue. Ultrastructural observations of periodontal polymorphonuclear leukocytes showed defective granulation, with abnormal granules not discharging their lysosomal content against engulfed bacteria. Viable dividing bacteria were found in the cytoplasm. CONCLUSIONS: In this case, early-onset periodontitis seems to be the expression of C-HS granulocyte deficiency. Periodontal treatment of these patients is often unsuccessful. This case report illustrates the importance of the dentist in initiating clinical and biological investigations in such early aggressive periodontitis in young patients.

Adolescent↗

PubMed1982

[Separation of mouse bone marrow cells by preparative electrophoresis].

Free-flow electrophoresis was used to separate mouse bone marrow cells. From five to eight fractions with an amount of cells sufficient for morphofunctional analysis could be obtained in different experiments. Granulocyte precursors were found in fractions with low electrophoretic mobility (EPM), whereas erythrocyte precursors in fractions with high EPM. CFUs were detected both in low and in high EPM fractions. In individual fractions the concentration of these cells was 4 times greater than in the initial cell suspension.

Animals↗

PubMed1999

Mitogen and substrate differentially affect the lineage restriction of adult rat subventricular zone neural precursor cell populations.

The effects of specific mitogens and substrates on the proliferative capacity and the differentiated phenotypic plasticity of neural precursor cell populations isolated from the adult rat subventricular zone (SVZ) were examined. SVZ cells were grown on uncoated tissue culture plastic, extracellular matrix, or poly-D-ornithine with either laminin or fibronectin. SVZ neural precursor cells could not be generated with platelet-derived growth factor (PDGF), granulocyte macrophage colony stimulating factor, stem cell factor, heparin-binding epidermal growth factor (HB-EGF), granulocyte colony stimulating factor, or ciliary neurotrophic factor (CNTF), but could be with EGF, fibroblast growth factor 2 (FGF2), and FGF2 plus heparin. Varying combinations of substrate and mitogen resulted in very different expansion rates and/or lineage potential. Neurons, oligodendrocytes, and astrocytes differentiated from all cultures, but EGF-generated neural precursor cells were more restricted to an astrocytic lineage and FGF2-generated neural precursor cells had a greater capacity for neuronal differentiation. In both EGF- and FGF2-generated cell populations, CNTF increased the number of differentiated astrocytes, triiodothyronine oligodendrocytes, PDGF neurons, and brain-derived neurotrophic factor neurons only from EGF cells. Electrophysiological analysis of differentiated cells showed three distinct phenotypes, glial, neuronal, and presumed precursor cells, although the neuronal properties were immature. Collectively, these data indicate that CNS neural precursor cell populations isolated with different mitogens and substrates are intrinsically different and their characteristics cannot be directly compared.

Animals↗

PubMed1975

[Kinetics of the main sections of the hematopoietic system in the process of postradiational regeneration].

After a sublethal (200 rad) irradiation of mice there occurred during the first 24 hours in the bone marrow a marked reduction of the number of the stem (to 4%), committed precursors of granulocytes and macrophages (to 20%) and of the morphologically-identified cells (to 50%). Complete restoration of hemopoiesis was observed by the end of the 2 weeks after the irradiation and was primarily due to the exponential growth of the number of the stem cells and their intensified proliferation. An increase in the number of the committed precursors was retarded to the moment of restoration of the normal amount of cells in the bone marrow.

Animals↗

PubMed2004

Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.

BACKGROUND: Endothelial progenitor cells (EPCs), derived from bone marrow, contribute to vessel repair and neovascularization. Because uremia is a state of endothelial dysfunction associated with high cardiovascular mortality, as well as a state of reduced hematopoiesis, we studied the number and function of EPCs in patients on long-term hemodialysis (HD) therapy. METHODS: We counted the number of EPCs in 20 HD patients and 16 healthy volunteers. To assess EPC function, we measured migratory activity, adhesion to matrix proteins, and adhesion to endothelial cells. Furthermore, we measured blood levels of vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor, factors known to influence EPC kinetics. Circulating precursor cells (CD34+ , CD34+ /CD133+ , CD34+ /KDR+ cells) were counted by means of flow cytometric analysis. RESULTS: The number of EPCs in HD patients was significantly elevated compared with controls (459.7 +/- 92 versus 364.8 +/- 77.4 EPC/high-power field). However, migratory activity was markedly decreased in HD patients (47.5 +/- 27.7 versus 84.7 +/- 3.2 EPC/high-power field). EPCs of HD patients showed impaired adhesion to extracellular matrix and endothelial cells. VEGF blood levels in HD patients were 2-fold greater compared with controls. The number of circulating CD34+ and CD34+ /133+ cells was reduced in HD patients. There were no differences in total numbers of CD34+ /KDR+ cells. CONCLUSION: This study shows an elevated number, but pronounced functional impairment, of EPCs in patients on long-term HD therapy. The latter may result in limited endothelial repair, which, in turn, may contribute to endothelial dysfunction in this particular group of patients.

AC133 Antigen↗

PubMed1994

Cell cycle kinetics of hematopoiesis before and after in vivo administration of GM-CSF in refractory anemia: evidence for a shortening of the granulocyte release time.

GM-CSF administration to patients with refractory anemia (RA) induces an increase in neutrophils and eosinophils. We studied cell kinetic mechanisms underlying this observation using clonogenic assays and in vivo iododeoxyuridine labeling of bone marrow cells. Cell cycle kinetics were studied in three patients before and during GM-CSF administration (two daily subcutaneous injections of 54 or 108 micrograms). No consistent effect on the relative number of bone marrow CFU-GM was noticed. The DNA synthesis time and potential doubling time of low-density bone marrow cells remained essentially the same. A slight decrease (1.5-3.7%) in labeling index was found, originating from the myelo(-mono)cytic lineage. In all three patients the release time of labeled granulocytes from the bone marrow into the peripheral blood was shortened (before GM-CSF treatment 5-7 days and during GM-CSF 3-4 days). Cell cycle kinetics of CD34+ cells were studied in order to obtain kinetic information on immature precursor and progenitor cells. The DNA synthesis time of the CD34+ cells was shortened during GM-CSF therapy, resulting in a shorter potential doubling time. GM-CSF administration to patients with RA results in a rise in granulocytes that might be due partly to an accelerated release of granulocytes from the bone marrow compartment into the circulating blood and partly to an increased proliferative activity of the immature precursor and progenitor cells.

Anemia, Refractory↗

PubMed1991

VpreB gene expression in hematopoietic malignancies: a lineage- and stage-restricted marker for B-cell precursor leukemias.

We show here that analysis of VpreB gene transcription can be a specific way to identify acute leukemias of cells at very early stages of B-cell development. Northern blot analysis of RNAs from 63 leukemia samples showed that VpreB RNA was present in malignancies of precursor B cells, the expression being a feature of both common acute lymphoblastic leukemia (ALL) (CD10+) and null ALL (CD10-). It was absent from malignancies of mature B cells (surface Ig positive), from acute leukemias of the T-cell lineage and granulocyte-macrophage lineages, and from normal tonsil B and T lymphocytes. Chronic myeloid leukemia blast crises of the B-precursor-cell type expressed the VpreB gene while myeloid blast crises did not. VpreB RNA was also expressed in the neoplastic cells of one of three patients with acute undifferentiated leukemias. These data show that VpreB RNA expression is a marker of the malignant forms of precursor B cells, and that it appears at least as early as cytoplasmic CD22 and CD19 in tumors of the B-cell lineage.

Blotting, Northern↗