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Biomedical subjects

C G Begley

Publications and source records attributed to C G Begley.

At least 181 records · Page 10Linked to original sources
PubMed1987

Quantitative responsiveness of murine hemopoietic populations in vitro and in vivo to recombinant multi-CSF (IL-3).

Purified, bacterially synthesized, recombinant Multi-CSF (rMulti-CSF) exhibited in vitro proliferative effects identical to those of native Multi-CSF on a broad range of progenitor cells from normal murine bone marrow and on the continuous cell line FD-CP1. The injection into normal adult mice of 6-200 ng purified rMulti-CSF three times daily for six days induced dose-related rises in peritoneal macrophages, neutrophils, and eosinophils, and in the spleen weight and content of megakaryocytes, mast cells, and progenitor cells, some responses being detectable with the lowest dose injected. No Multi-CSF was detected in the serum, organ extracts, or organ-conditioned medium from normal or endotoxin-injected mice. While the data indicate that even small doses of injected rMulti-CSF can produce detectable hemopoietic changes in normal adult mice, the pattern of these changes and the failure to detect Multi-CSF in vivo raise doubts that Multi-CSF plays a significant role as a regulator of hemopoiesis in normal adult life.

Animals↗
PubMed1987

Transfusion-dependent beta-thalassemia: in vitro characterization of peripheral blood multipotential and committed progenitor cells.

Conditions for the in vitro culture of multipotential and committed progenitor cells obtained from the peripheral blood of transfusion-dependent beta-thalassemic individuals have been determined. When stimulated by either human placental-conditioned medium (HPCM), phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM), or U5637-conditioned medium and erythropoietin, colonies containing neutrophils, neutrophils and macrophages, macrophages, eosinophils, erythroid cells, or mixtures of erythroid cells and neutrophils, eosinophils, or macrophages were obtained in cultures of beta-thalassemic mononuclear cells. Removal of adherent cells from beta-thalassemic peripheral blood demonstrated the presence of cells capable of the autostimulation of all of the above colony types in the presence of erythropoietin. In addition, adherent cells also appeared to inhibit erythropoiesis in cultures stimulated with HPCM. In cultures of nonadherent beta-thalassemic mononuclear cells, one population of BFU-E was stimulated by erythropoietin and a second required both erythropoietin and HPCM. Titration of erythropoietin, in the presence of optimal stimulation by HPCM, showed that beta-thalassemic peripheral blood BFU-E were more responsive to erythropoietin than was normal peripheral blood BFU-E. Stimulation of multipotential cells in cultures of nonadherent mononuclear cells was dependent upon HPCM. Using these culture conditions, the studies show that, compared with normals, the peripheral blood of transfusion-dependent beta-thalassemic patients contain elevated numbers of multipotential and committed progenitor cells, and that splenectomy did not account for the elevated numbers of these cells.

Cells, Cultured↗
PubMed1986

Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells.

A purified murine lymphokine, eosinophil differentiation factor (EDF), was found to be a selective stimulus for the clonal proliferation and differentiation of murine eosinophil progenitor cells, establishing it as the murine eosinophil colony-stimulating factor (Eo-CSF). EDF was also active on human eosinophil progenitors and mature blood eosinophils, but had no effect on neutrophil or macrophage precursor cells, nor on blood neutrophils. In culture of human bone marrow cells, EDF stimulated equal numbers and equal sizes of eosinophil colonies to develop when compared with human placental conditioned medium, a source of human CSFs, suggesting that all responsive progenitor cells were stimulated. Clone transfer experiments and the linear relationship between number of bone marrow cells plated and colonies produced confirmed that the action of EDF was directly on eosinophil progenitor cells. EDF increased the capacity of human blood eosinophils, but not neutrophils, to kill antibody-coated tumor cells and to phagocytose serum-opsonized yeast cells. This functional activation was associated with the enhanced expression of functional antigens (GFA-1, GFA-2, and the receptor for C3bi) on eosinophils. The possession by EDF (Eo-CSF) of all the properties expected of a human eosinophil CSF raises the possibility that a human analog of this molecule exists, and is involved in the regulation of production and function of human eosinophils in vivo.

Animals↗
PubMed1986

The IIb-IIIa glycoprotein complex that mediates platelet aggregation is directly implicated in leukocyte adhesion.

Evidence is presented that the IIb-IIIa glycoprotein complex, which functions as the receptor for fibrinogen on platelets and is central to platelet aggregation, is expressed on the surface of leukocytes where it may function as a receptor for fibronectin. F(ab')2 fragments of a monoclonal antibody, 25E11, raised against activated large granular lymphocytes, inhibited killing by natural killer cells, blocked the binding of fibronectin-coated particles by monocytes, and stimulated neutrophils to exhibit increased antibody-dependent killing. Immunoprecipitation studies of leukocytes and platelets, and the ability of 25E11 to inhibit platelet aggregation, identified the antigen as an epitope on the IIb-IIIa complex. This glycoprotein thus constitutes the first example of a receptor mediating both platelet aggregation and leukocyte adhesion.

Adult↗
PubMed1986

Hemopoietic effects of purified bacterially synthesized multi-CSF in normal and marrow-transplanted mice.

Normal adult mice and irradiated, marrow-transplanted mice were injected three times daily for 6 days with 200 ng purified bacterially synthesized recombinant Multi-CSF. Normal mice responded with increased peritoneal macrophages, eosinophils and neutrophils, spleen weight increases and major increases in spleen mast cells and hemopoietic progenitor cells. Irradiated, marrow-transplanted mice failed to develop large increases in peritoneal cell numbers but did show rises in spleen weight, marrow cellularity and spleen and marrow progenitor cell levels. The results confirm data indicating a regulatory role for Multi-CSF in vivo and suggest that Multi-CSF may be of some value in accelerating hemopoietic regeneration following marrow transplantation.

Animals↗
PubMed1986

Diflunisal-induced neutropenia.

We report a case of neutropenia associated with the use of diflunisal. The neutropenia occurred with initial administration and on subsequent inadvertent rechallenge with the drug. Bone marrow biopsy showed active granulopoiesis and an immune-mediated mechanism for this response is postulated.

Agranulocytosis↗
PubMed1986

Recombinant human granulocyte-macrophage colony-stimulating factor stimulates in vitro mature human neutrophil and eosinophil function, surface receptor expression, and survival.

A purified recombinant human granulocyte-macrophage colony stimulating factor (rH GM-CSF) was a powerful stimulator of mature human eosinophils and neutrophils. The purified rH GM-CSF enhanced the cytotoxic activity of neutrophils and eosinophils against antibody-coated targets, stimulated phagocytosis of serum-opsonized yeast by both cell types in a dose-dependent manner, and stimulated neutrophil-mediated iodination in the presence of zymosan. In addition, rH GM-CSF enhanced N-formylmethionylleucylphenylalanine(FMLP)-stimulated degranulation of Cytochalasin B pretreated neutrophils and FMLP-stimulated superoxide production. In contrast, rH GM-CSF did not promote adherence of granulocytes to endothelial cells or plastic surfaces. rH GM-CSF selectively enhanced the surface expression of granulocyte functional antigens 1 and 2, and the Mo1 antigen. rH GM-CSF induced morphological changes and enhanced the survival of both neutrophils and eosinophils by 6 and 9 h, respectively. These experiments show that granulocyte-macrophage colony stimulating factor can selectively stimulate mature granulocyte function.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1986

Effects of purified bacterially synthesized murine multi-CSF (IL-3) on hematopoiesis in normal adult mice.

Normal adult C57BL, BALB/c, and C3H/HeJ mice were injected intraperitoneally three times daily for up to 6 days with 102,000 U (200 ng) per injection of purified, bacterially synthesized, Multipotential colony-stimulating factor (CSF) (Interleukin-3) (rMulti-CSF) and compared with control mice injected with serum/saline with or without added endotoxin (1 ng/mL). Mice injected with rMulti-CSF exhibited tenfold rises in blood eosinophil and twofold to threefold rises in neutrophil and monocyte levels. The spleens from mice injected with rMulti-CSF showed a 50% increase in weight, elevated levels of maturing granulocytes, eosinophils, nucleated erythroid cells and megakaryocytes, and up to 100-fold rises in mast cells. Progenitor cell frequencies in the spleen were elevated sixfold to 18-fold. No significant changes were observed in the marrow. Sixfold to 15-fold rises were observed in peritoneal cell populations of mice injected with rMulti-CSF with evidence of increased peritoneal macrophage phagocytic activity. Livers of C57BL mice, but not of the other strains, exhibited increased numbers of infiltrating hematopoietic cells whereas rises in mast cell numbers were observed in the mesenteric lymph node, skin, and gut in BALB/c and C3H/HeJ mice. Endotoxin was excluded as being responsible for the observed changes except possibly those involving peritoneal macrophage phagocytic activity. The results indicate that the injection of normal mice with rMulti-CSF significantly stimulates the same types of hematopoietic populations as are stimulated in vitro by Multi-CSF and indicate that this and other CSFs should be useful in stimulating hematopoietic repopulation and functional activity in vivo.

Animals↗
PubMed1986

Biologic properties in vitro of a recombinant human granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) was purified to homogeneity from medium conditioned by COS cells transfected with a cloned human GM-CSF cDNA and shown to be an effective proliferative stimulus in human marrow cultures for GM and eosinophil colony formation. The specific activity of purified rH GM-CSF in human marrow cultures was calculated to be at least 4 X 10(7) U/mg protein. Clone transfer experiments showed that this proliferation was due to direct stimulation of responding clonogenic cells. Acting alone, rH GM-CSF did not stimulate erythroid colony formation, but in combination with erythropoietin, increased erythroid and multipotential colony formation in cultures of peripheral blood cells. rH GM-CSF had no proliferative effects on adult or fetal murine hematopoietic cells, did not induce differentiation in murine myelomonocytic WEHI-3B cells, and was unable to stimulate the survival or proliferation of murine hematopoietic cell lines dependent on murine multi-CSF (IL 3). rH GM-CSF stimulated antibody-dependent cytolysis of tumor cells by both mature human neutrophils and eosinophils and increased eosinophil autofluorescence and phagocytosis by neutrophils. From a comparison of these effects with those of semipurified preparations of human CSF alpha and -beta, it was concluded that rH GM-CSF exhibited all the biologic activities previously noted for CSF alpha.

Animals↗
PubMed1986

Purified colony-stimulating factors enhance the survival of human neutrophils and eosinophils in vitro: a rapid and sensitive microassay for colony-stimulating factors.

The survival of purified human blood neutrophils and eosinophils was monitored using microwell cultures. Survival was enhanced in cultures containing human or murine colony-stimulating factors (CSFs). The survival of both cell types was enhanced by purified recombinant human granulocyte-macrophage CSF and partially purified preparations of the native molecule, CSF alpha. Neutrophil but not eosinophil survival was enhanced by murine granulocyte-CSF and its human analogue CSF beta. Eosinophil but not neutrophil survival was enhanced by murine eosinophil differentiation factor (eosinophil CSF). The mature cell survival provided an assay system for CSF that was 10(2) to 10(3) more sensitive than the standard assay of stimulation of colony formation in agar cultures and could be completed within 48 hours. These results demonstrated that CSF induced and enhanced survival of mature human neutrophils and eosinophils in vitro. Furthermore, the lineage specificity of purified murine CSFs was retained in their action on human cells.

Animals↗
PubMed1985

TLiSA1, a human T lineage-specific activation antigen involved in the differentiation of cytotoxic T lymphocytes and anomalous killer cells from their precursors.

The characteristics of a novel T lineage-specific activation antigen, termed TLiSA1, are described. The antigen was detected with a mouse monoclonal antibody, LeoA1, that was raised against activated human T cells generated in mixed lymphocyte culture (MLC). The antigen became strongly expressed on T cells 48-72 h after stimulation with phytohemagglutinin, and retained expression on MLC-activated T cells after 10 d of culture. The antigen was absent from a range of human T, B, myeloid, fibroblast, and tumour cell lines, but was present on the surface of the interleukin 2 (IL-2)-dependent gibbon cell line MLA-144. Analysis of the antigen by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of immunoprecipitates obtained from activated human T cells demonstrated a broad band in the region of 70 kD, whereas precipitates obtained from MLA-144 revealed a single narrow band of 95 kD. The molecule was expressed with a maximum density of 66,000 copies per cell on the surface of MLC-activated T cell blasts, as assessed by Scatchard analysis. TLiSA1 was distinguished from the IL-2 receptor bound by the anti-Tac monoclonal antibody by demonstrating that the antigens did not comodulate or coprecipitate, and by constructing an IL-2-independent human T X T hybrid that expressed the TLiSA1 but not the Tac antigen. MLC with B lymphoblasts was used to generate cytotoxic T lymphocytes (CTL) specific for the stimulating cell, and anomalous killer (AK) cells able to kill melanoma target cells. The presence of LeoA1 or F(ab')2 fragments of the antibody from the beginning of coculture did not affect proliferation in these cultures, but did inhibit the induction of both CTL and AK cells from their precursors. This inhibition of differentiation by LeoA1 was confirmed under conditions of limiting dilution, where it was shown that the antibody reduced the frequency of CTL produced, and greatly (fourfold) reduced the frequency of AK cells generated from their precursors. We discuss the possibility that human CTL may express a differentiation factor receptor that is distinct from the receptor for IL-2.

Adult↗
PubMed1985

Spontaneous improvement in pancreatic function in chronic pancreatitis.

Three women with chronic pancreatitis who were observed for 4-29 years showed spontaneous improvement in exocrine function as assessed by symptoms and by reduction in fecal excretion of fat. One patient had a reduction in the severity of diabetes mellitus, while another showed a progressive increase in the maximum bicarbonate concentration in duodenal juice after the intravenous injection of secretin. Improvement in pancreatic function followed cessation of alcohol in two patients in whom chronic pancreatitis was associated with alcohol abuse.

Adult↗
PubMed1985

The proliferative effects of human GM-CSF alpha and beta and murine G-CSF in microwell cultures of fractionated human marrow cells.

Blast cell-enriched and promyelocyte-myelocyte-enriched fractions of human marrow were prepared by fluorescence-activated cell sorting using an antineutrophil monoclonal antiserum. Cells from both fractions proliferated in microwell cultures when stimulated by placental or bladder cancer cell conditioned medium containing colony stimulating factor. Semipurified preparations of both GM-CSF alpha and beta from bladder cancer cell conditioned medium were effective proliferative stimuli for both cell populations. Pure murine G-CSF, GM-CSF, M-CSF and Multi-CSF failed to stimulate detectable proliferation in blast cell fractions containing granulocyte-monocyte progenitors. However, G-CSF was an effective proliferative stimulus for human promyelocytes and myelocytes leading to the formation of differentiating granulocytic progeny. G-CSF also stimulated the proliferation of human promyelocytic leukemic cells. Promyelocyte-myelocyte-enriched fractions of human marrow appear to be useful target cells for monitoring the proliferative effects of human-active CSFs in microwell cultures.

Animals↗
PubMed1985

Another immune-mediated disease associated with hairy cell leukemia: chronic active hepatitis.

This report describes a case of hairy cell leukemia (HCL) occurring with autoimmune chronic active hepatitis (CAH). A 74-year-old woman presented with typical clinical and histologic features of HCL for which splenectomy was performed. 2 years later she developed abnormal liver function tests due to auto-immune CAH. The liver function tests improved promptly after prednisolone therapy. HCL has been reported to occur with several immune-mediated diseases including polyarteritis nodosa, rheumatoid arthritis, hemolytic anemia, cutaneous vasculitis and monoclonal gammopathy with amyloidosis. This report adds a further example of HCL coexisting with an immune-mediated disease, in this case autoimmune CAH.

Aged↗
PubMed1985

The clonal proliferation in vitro of enriched populations of human promyelocytes and myelocytes.

The proliferative capacity of normal human promyelocytes and myelocytes was demonstrated and characterized on the basis of clonal proliferation in agar. An enriched population of normal human promyelocytes and myelocytes was obtained from bone marrow using the monoclonal antibody WEM G11 and the fluorescence-activated cell sorter (FACS). In cultures stimulated by placental-conditioned medium, these cells generated peak total clone numbers between days 3 and 5 of culture. Clones disappeared rapidly thereafter. These clones were mainly of subcolony size at day 7, although some colonies were generated by this population. The clones were primarily neutrophilic in type. These cells had a plating efficiency of up to 50%, and clonal proliferation was dependent on stimulation by colony-stimulating factor (CSF).

Antibodies, Monoclonal↗
PubMed1985

Fractionated populations of normal human marrow cells respond to both human colony-stimulating factors with granulocyte-macrophage activity.

Populations of normal human colony-forming cells (blast cells) and cluster-forming cells (promyelocytes-myelocytes) were obtained from bone marrow by using the monoclonal antibody WEM G11 and the fluorescence-activated cell sorter (FACS). Both populations were shown to be responsive to both human colony-stimulating factors (CSFs) with granulocyte-macrophage activity (CSF alpha and CSF beta), with the cluster-forming cell population being more responsive to CSF beta than the colony-forming cell population. The clonal proliferation of promyelocytes-myelocytes was transient, and the clones generated were of subcolony size (less than 40 cells) regardless of the CSF used. Clone transfer experiments demonstrated that progeny of promyelocytes-myelocytes initiated using one stimulus (CSF alpha or CSF beta) were also responsive to the other stimulus.

Animals↗
PubMedDate not supplied

Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells.

We have recently purified murine granulocyte colony-stimulating factor (G-CSF), a regulatory glycoprotein which stimulates granulocyte colony formation from committed murine precursor cells in semi-solid agar cultures. G-CSF is one of a family of colony-stimulating factors that regulate the growth and differentiation of granulocytes and macrophages. While the other murine CSFs (granulocyte-macrophage (GM)-CSF, macrophage (M)-CSF and multi-CSF) show little or no differentiation-inducing activity on murine myelomonocytic leukaemia cell lines, G-CSF (or MGI-2(6)) is able to induce the production of terminally differentiated cells from WEHI-3B and other myeloid leukaemia cell lines. More importantly, G-CSF-containing materials suppress the self-renewal of myeloid leukaemia stem cells in vitro and the leukaemogenicity of treated myeloid leukaemic cells in vivo. It is important to identify the human analogue of murine G-CSF so that its effectiveness on human myeloid leukaemia cells can be assessed. Here we show that an analogue of G-CSF does exist among the CSFs produced by human cells and that the murine and human molecules show almost complete biological and receptor-binding cross-reactivities to normal and leukaemic murine or human cells. The human G-CSF analogue is identified as a species of CSF that we have previously described as CSF-beta.

Animals↗