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Results for “Colony-Stimulating Factors”

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PubMed1976

Human preleukaemia cell culture studies in sideroblastic anaemia.

Cell structure abnormalties are found in acute leukaemia and preleukaemic states. Studies on bone marrow cells and peripheral leucocytes of 4 patients with idiopathic acquired sideroblastic anaemia showed patterns in cell culture similar to those reported in acute leukaemia: 2 of these patients later developed leukaemia. Other patients with idiopathic, secondary or congenital sideroblastosis showed no such cell culture abnormalities, and none developed leukaemia. Studies such as this suggest that cell culture methods detect altered cellular function preceding overt leukaemia and that these abnormal findings may be helpful in the evaluation of patient groups with an increased incidence of leukaemia.

Anemia, Sideroblastic↗
PubMed2026

Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

Adult↗
PubMed1979

Current concepts of abnormal stem cell proliferation in human disease.

Using acute myeloid leukemia as an example, the concept of abnormal hematopoietic stem cell production has been examined. It is concluded that the major problem does not lie in humoral regulators, either stimulators or inhibitors, of stem cell production but in intrinsic cellular defects which do not allow cells to respond to these materials. The nature of the stem cell defects has not been defined. Similar mechanisms appear to exist in other human hematopoietic disorders in which abnormal stem cell proliferation is a major feature.

Animals↗
PubMed2026

Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.

Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.

Humans↗
PubMed2026

CRISPR screening identifies DTX4 governing alveolar macrophage cholesterol efflux in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain incompletely defined. Here, through a genome-wide CRISPR screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify DTX4 as a pivotal regulator of cholesterol efflux in AMs. In mice, AAV-mediated silencing of DTX4 led to excessive AM lipid accumulation, exacerbated proteinosis, increased lung opacities, and deteriorated pulmonary function. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. Conversely, AM-specific overexpression of DTX4 in the Csf2ra-/- PAP model markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities, and rescued pulmonary function. Mechanistically, DTX4 stabilizes the GM-CSF receptor via an E3-independent interaction to sustain JAK2/STAT5 signaling, which reciprocally maintains DTX4 transcription. This positive-feedback loop drives PPARγ expression, and its disruption in PAP impairs cholesterol efflux, a defect partially reversible by ectopic PPARγ expression. Collectively, our findings identify DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP.

Animals↗
PubMed1978

Immunologic functions and in vitro activation of cultured macrophage tumor lines.

Five murine monocyte of macrophage tumor lines adapted to culture were characterized for differentiated properties. They ingested zymosan and latex beads, bore receptors for immunoglobulin and complement, synthesized lysozyme (most of which was secreted), and produced granulocyte colony-stimulating activity, either spontaneously or inducibly. Some of the lines also mediated phagocytosis and exocytosis of red blood cells (RBC) and lysis of tumor targets, dependent on the presence of specific antitarget sera. All the lines were growth inhibited by zymosan and Mycobacterium bovis BCG, but not by latex beads. Other macrophage-activating agents, dextran sulfate and lipopolysaccharide (LPS), as well as tuberculin purified protein derivative (PPD), inhibited most of the lines. Except for Fc and C receptors, most of the above properties were not found with other types of hematopoietic tumors in culture. In attempts to activate the macrophage lines in vitro to the "angry" state, we found that preincubation with concentrations of LPS and PPD cytostatic to the cells stimulated antibody-dependent RBC lysis, but not antibody-independent or tumor cytolysis. A classification of monocyte-related tumors and normal cells is proposed based on functional activities and differential sensitivity to immunostimulating agents.

Animals↗
PubMed1979

Growth enhancement and serum replacement in cloning of murine mastocytoma and granulocyte/macrophage precursor cells: two distinct activities present in hemolysates.

In the present study we investigated the serum replacing and enhancing activities of erythrocyte lysates, obtained from different animal species, on the growth of murine mastocytoma cells and normal granulocyte/macrophage precursor cells (CFU-C) present in bone marrow. The soft agar technique for cloning hemopoietic cells in vitro was used to quantitate the growth of these cells in culture. Rat, rabbit, guinea pig, mouse and sheep hemolysates were tested for their capacity to replace or to enhance serum as a growth promoter. All hemolysates except mouse were able to replace serum efficiently when mastocytoma cells were cloned. On the other hand, only rat hemolysate proved to be efficient for cloning normal murine CFU-C. Since increasing the concentration of hemolysates in the soft agar medium did not change these results, the differences in activity are unlikely to reflect quantitative variations. However, hemolysates with little or no serum replacing capacity enhanced the clonal growth of normal CFU-C when added to small amounts (2.5%) of horse serum. Trypsin treatment of rat hemolysate destroyed its serum replacing capacity but not its enhancing activity. No correlation was found between the amount of hemoglobin and the replacing activity of each hemolysate. The data obtained in the present study point to the presence of at least two distinct activities in hemolysate: serum replacing and growth enhancing capacities.

Animals↗
PubMed1977

Functional and morphologic characterization of human T cells continuously grown in vitro.

Long-term growth (now over 13 months) of thymus-derived lymphocytes from numerous normal human bone marrow and peripheral blood cell samples was accomplished by using a factor present in media obtained from mitogen-stimulated human peripheral blood lymphocytes. This long-term growth could neither be initiated nor maintained by mitogens alone. All cell cultures were greater than 90% E rosette-positive, whereas the tests for B cell markers, surface IgG and IgM, and EAC rosette were routinely negative. There was no evidence for the presence of granulocytes, monocytes, and their precursors in these cultures. The E rosette-positive cells were then tested to see if they had T cell functions. PHA, Con A, and pokeweed mitogens stimulated lymphproliferative responses in these cultures comparable to those of fresh peripheral blood cells. These proliferating cells were also able to release cell mediators, such as interferon and colony-stimulating activity. Further evidence for the T lymphocyte nature of these cultured cells was obtained from one-way mixed leukocyte cultures in which these cells responded to but were unable to stimulate allogeneic cells. The functional and morphologic characteristics of these cultured cells show that these cells are T cells that grow continuously in vitro.

Cells, Cultured↗
PubMed1978

Macrophage colony development: properties of colony stimulating factors from murine embryo and pregnant uterus.

Extracts from embryonic and uterine tissue of mice, operationally defined as colony stimulating factor (CSF), promoted the growth of macrophage-granulocyte colonies in vitro. Uterine CSF focusses from pH 5.15 to 6.00 and embryonic CSF from pH 3.60 to 5.20, although both forms have similar biological activity. CSF is relatively resistant to denaturation but it is inactivated by periodate and dithiothreitol. Gel filtration indicates a molecular weight of 45,000 which is unchanged following treatment with insolubilized trypsin, a procedure which affords a useful purification (240-fold). Trypsin-sensitive material in CSF preparations modifies colonial form under certain conditions of culture, probably by increasing the motility of macrophages. Diaminoethane derivatives of CSF were prepared and retained biological activity at isoelectric points above pH 9.0. These derivatives may be covalently linked to Sepharose providing an insolubilized form of CSF to study interactions of CSF with the cell surface.

Animals↗
PubMed1975

Regulation of blood cell diferentiation.

The hemopoietic (blood forming) system contains pluripotent stem cells able to give rise to a variety of differentiated progeny, including erythrocytes, granulocytes, megakaryocytes, monocytes, macrophages, and possible other cell types. Although a good deal is known about cell lineage relationships in the hemopoietic system, only limited information is available about the mechanisms regulating the proliferation and differentiation of the stem cells and their progeny. An approach to this latter problem has been provided by the develoment of new techniques for the cultivation of hemopoietic cells in short-term cultures. In such cultures, the proliferation and differentiation of hemopoietic cells can be studied under controlled conditions. Two areas of investigation show particular promise: elucidation of the role of the cell surface membrane in regulation; and the possible development, through a detailed investigation of the properties of leukoviruses, of new methods for the genetic analysis of hemopoietic cells.

Animals↗