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Experimental Hematology May 2016High-dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for younger patients with newly diagnosed multiple myeloma and...
High-dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for younger patients with newly diagnosed multiple myeloma and is aimed at achieving as deep and complete a response as possible after various combinations of induction therapy. However, it is frequently associated with infectious complications. This study investigated the effects of high-dose treatment with autologous stem cell support on patients' innate immunity, with a focus on subpopulations and functioning of recently released polymorphonuclear leukocytes (PMNs) and monocytes in peripheral blood. Flow cytometry-based analysis was used to measure the degree of PMN maturation and activation, before and after ASCT and compared with healthy controls. After high-dose treatment and ASCT, a smaller proportion of patients' PMNs had the capacity for oxidative burst. Moreover, patients' PMNs, both before and after ASCT, had a reduced capacity for phagocytosis. Eosinophils, which recently have been suggested to play a role in promoting malignant plasma cell proliferation, were markedly reduced after ASCT, with slow regeneration. HLA-DR expression by monocytes was significantly depressed after ASCT, a characteristic often attributed to monocytic myeloid-derived suppressor cells. Our results suggest that several aspects of phagocytic function are impaired for at least 20 days after ASCT.
Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dose-Response Relationship, Drug; Eosinophils; Escherichia coli; Female; HLA-DR Antigens; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Monocytes; Multiple Myeloma; Neutrophils; Phagocytes; Phagocytosis; Respiratory Burst; Time Factors; Transplantation, Autologous
PubMed: 26774385
DOI: 10.1016/j.exphem.2016.01.002 -
Journal of Immunology (Baltimore, Md. :... Mar 2006Adhesion is a fundamental cellular response that is essential to the physiologic processes of development, differentiation, proliferation, and motility, as well as to...
Adhesion is a fundamental cellular response that is essential to the physiologic processes of development, differentiation, proliferation, and motility, as well as to the pathology of inflammation, transformation, and metastasis. Adhesion of phagocytic leukocytes is a critical modulator of antimicrobial and cytotoxic functions, including the respiratory burst, secretion, and apoptosis. Because phospholipase D (PLD) is linked to several signaling pathways implicated in these processes, we tested the hypothesis that PLD regulates phagocyte adhesion. Adhesion of primary human neutrophils and monocyte-derived macrophages to fibronectin was accompanied by marked stimulation of PLD activity. Similarly, adhesion of both human (PLB, THP-1) and murine (RAW) myeloid-macrophage cell lines to fibronectin, fibrinogen, collagen, or plastic resulted in significant activation of PLD. Stimulation of PLD activity was rapid and persisted for at least 90 min. Confocal microscopy indicated that PLD1 exhibited partial colocalization with actin filaments at the adherent interface, in proximity to the focal adhesion protein, paxillin. Reductions in PLD activity by chemical inhibitors or specific short-interfering RNA-induced knockdown of PLD1 resulted in significant inhibition of phagocyte adhesion and was accompanied by reductions in total cellular F-actin. These data support the hypotheses that adhesion stimulates PLD activity, and that PLD1 regulates the initial stages of phagocyte adhesion. Stimulation of PLD activity may promote adhesion-dependent phagocyte effector responses.
Topics: Actins; CD18 Antigens; Cell Adhesion; Cell Differentiation; Cells, Cultured; Humans; Lymphocytes; Myeloid Cells; Phagocytes; Phospholipase D; RNA Interference
PubMed: 16517737
DOI: 10.4049/jimmunol.176.6.3686 -
Journal of Leukocyte Biology Jan 2015
Topics: Animals; History, 20th Century; Humans; NADPH Oxidases; Phagocytes; Respiratory Burst
PubMed: 25351512
DOI: 10.1189/jlb.4CE0714-352R -
Journal of Leukocyte Biology Nov 2010Triggering of phagocyte apoptosis is a major virulence mechanism used by some successful bacterial pathogens. A central issue in the apoptotic death context is that...
Triggering of phagocyte apoptosis is a major virulence mechanism used by some successful bacterial pathogens. A central issue in the apoptotic death context is that fully developed apoptosis results in necrotic cell autolysis (secondary necrosis) with release of harmful cell components. In multicellular animals, this occurs when apoptosing cells are not removed by scavengers, mainly macrophages. Secondary necrotic lysis of neutrophils and macrophages may occur in infection when extensive phagocyte apoptosis is induced by bacterial cytotoxins and removal of apoptosing phagocytes is defective because the apoptotic process exceeds the available scavenging capacity or targets macrophages directly. Induction of phagocyte secondary necrosis is an important pathogenic mechanism, as it combines the pathogen evasion from phagocyte antimicrobial activities and the release of highly cytotoxic molecules, particularly of neutrophil origin, such as neutrophil elastase. This pathogenicity mechanism therefore promotes the unrestricted multiplication of the pathogen and contributes directly to the pathology of several necrotizing infections, where extensive apoptosis and necrosis of macrophages and neutrophils are present. Here, examples of necrotizing infectious diseases, where phagocyte secondary necrosis is implicated, are reviewed.
Topics: Animals; Apoptosis; Autolysis; Bacterial Infections; Bass; Necrosis; Phagocytes; Phagocytosis; Signal Transduction; Virulence
PubMed: 20566623
DOI: 10.1189/jlb.0410205 -
Magnesium Research Mar 2010Epidemiological and experimental studies underline the role of magnesium in inflammation. Several data indicate an enhanced response of phagocytes (granulocytes,...
Epidemiological and experimental studies underline the role of magnesium in inflammation. Several data indicate an enhanced response of phagocytes (granulocytes, macrophages) derived from magnesium-deficient animals or cultured under low magnesium conditions to the inflammatory mediators' stimulation. On the contrary, it was pointed out that high extracellular Mg2+ concentration might partially attenuate the activation of phagocyte leukocytes. Thus, it is likely that magnesium-deficient conditions lead to the priming (pre-activation) of phagocytic cells. Magnesium status is an important modulator of the phagocyte response to immune stimuli and consequently could be implicated in a wide range of pathophysiological issues, e.g. those related to the production of radical oxygen species (ROS). It is likely that magnesium directly modulates phagocyte priming by its calcium antagonism and indirectly by its effect on the immunoinflammatory processes, the source of the priming mediators.
Topics: Animals; Humans; Inflammation; Magnesium; Oxidative Stress; Phagocytes
PubMed: 20228008
DOI: 10.1684/mrh.2009.0201 -
Clinical Immunology and Immunopathology Jul 1986Mononuclear phagocytes originate from stem cells in the bone marrow which differentiate from monoblasts into promonocytes, then into circulating blood monocytes.... (Review)
Review
Mononuclear phagocytes originate from stem cells in the bone marrow which differentiate from monoblasts into promonocytes, then into circulating blood monocytes. Subsequently the monocytes can develop into macrophages and reside in a variety of tissues. Mononuclear phagocytes have cell surface receptors for a variety of substances (e.g., IgG, complement components, fibronectin, and sugars) and are capable of secreting a number of mediators (enzymes, complement components, coagulation components, and monokines). The tissue macrophages adapt to their environment and express unique differentiated functions that are related to various anatomic sites and organs (e.g., Kupffer cells, pulmonary alveolar macrophages, osteoclasts, microglia). Macrophages have the capacity to become "activated" by both specific and nonspecific immunologic stimuli and the "activated" macrophage has enhanced functional capabilities (e.g., tumoricidal, microbicidal, phagocytosis, secretion of mediators). Abnormal monocyte/macrophage function may be acquired or may be due to genetic or developmental disorders. Because of their central role in host defense (in inflammatory responses, in antigen presentation, and in immunoregulatory networks), monocyte/macrophage dysfunction may result in one or more pathophysiologic consequences: defects in monocyte maturation, deficiencies in the clearance of physiologic substrates in lysosomal diseases (e.g., Gaucher's disease, mucopolysaccharidoses, osteopetrosis, metachromatic leukodystrophy), decreased synthesis and secretion of mediators (complement component deficiencies), defects in microbicidal activity (chronic granulomatous disease) and defects which are acquired following infection and during chemotherapy (e.g., acquired immune deficiency syndrome).
Topics: Bone Marrow Transplantation; Cell Cycle; Cell Differentiation; Humans; Lysosomes; Macrophages; Monocytes; Phagocyte Bactericidal Dysfunction; Receptors, Fc
PubMed: 3521970
DOI: 10.1016/0090-1229(86)90069-3 -
FEBS Letters Jul 2010Human phagocyte-specific chitotriosidase is part of innate immunity and shows anti-fungal activity towards chitin-containing fungi. We investigated the effect of...
Human phagocyte-specific chitotriosidase is part of innate immunity and shows anti-fungal activity towards chitin-containing fungi. We investigated the effect of stimulation of the C-type lectin receptor dectin-1 by beta-1,3-glucan (curdlan) on chitotriosidase expression and release by human phagocytes. We observed that curdlan triggers chitotriosidase release from human neutrophils. In addition, we show that curdlan impairs chitotriosidase induction in monocytes. Finally, curdlan temporarily induces chitotriosidase in enzyme-expressing monocyte-derived macrophages, followed by reduction of chitotriosidase expression after prolonged stimulation. These data on regulation of phagocyte-specific chitotriosidase following curdlan recognition support an important role of chitotriosidase in the elimination of chitin-containing pathogens.
Topics: Cell Differentiation; Chitin; Hexosaminidases; Humans; Immunity, Innate; Lectins, C-Type; Macrophages; Membrane Proteins; Monocytes; Nerve Tissue Proteins; Neutrophils; Phagocytes; beta-Glucans
PubMed: 20541547
DOI: 10.1016/j.febslet.2010.06.001 -
Advances in Experimental Medicine and... 1979Monocytes derived from peripheral blood of patients with familial Mediterranean fever (F.M.F.) demonstrated lower phagocytic capacity for Shigella flexneri and depressed...
Monocytes derived from peripheral blood of patients with familial Mediterranean fever (F.M.F.) demonstrated lower phagocytic capacity for Shigella flexneri and depressed bactericidal activity against S. albus when compared to monocytes from healthy individuals. Treatment of patients with colchicine did not alter these functions. On the other hand, chemokinesis of PMN of F.M.F. patients was enhanced especially during attacks. Colchicine treatment decreased significantly the PMN chemotactic migration.
Topics: Adolescent; Adult; Aged; Blood Bactericidal Activity; Chemotaxis, Leukocyte; Familial Mediterranean Fever; Female; Humans; Lipopolysaccharides; Male; Middle Aged; Monocytes; Neutrophils; Phagocytes; Phagocytosis; Shigella flexneri; Staphylococcus
PubMed: 397753
DOI: 10.1007/978-1-4684-8914-9_33 -
Frontiers in Immunology 2019The phagosome microenvironment maintains enzyme activity and function. Here we compared the phagosomal pH of human neutrophils, monocytes, dendritic cells (DC), and...
The phagosome microenvironment maintains enzyme activity and function. Here we compared the phagosomal pH of human neutrophils, monocytes, dendritic cells (DC), and monocyte-derived cells. An unexpected observation was the striking difference in phagosomal environment between the three monocytes subsets. Classical monocytes and neutrophils exhibited alkaline phagosomes, yet non-classical monocytes had more acidic phagosomes, while intermediate monocytes had a phenotype in-between. We next investigated the differences between primary naïve DC vs. monocyte-derived DC (MoDC) and established that both these cells had acidic phagosomal environments. Across all phagocytes, alkalinization was dependent upon the activity of the NADPH oxidase activity, demonstrated by the absence of NADPH oxidase from a patient with chronic granulomatous disease (CGD) or the use of a pharmacological inhibitor, diphenylene iodonium (DPI). Interestingly, MoDC stimulated with bacterial lipopolysaccharide had increased phagosomal pH. Overall, the increase in alkalinity within the phagosome was associated with increased oxidase activity. These data highlight the heterogeneous nature and potential function of phagocytic vacuoles within the family of mononuclear phagocytes.
Topics: Biomarkers; Cellular Microenvironment; Dendritic Cells; Humans; Hydrogen-Ion Concentration; Immunophenotyping; Lysosomes; Monocytes; NADPH Oxidases; Neutrophils; Oxidation-Reduction; Phagocytes; Phagocytosis; Phagosomes
PubMed: 30881356
DOI: 10.3389/fimmu.2019.00188 -
Journal of Immunological Methods Aug 2015We feature a multi-parametric approach based on an imaging flow cytometry platform for examining phagocyte antimicrobial responses against the gram-negative bacterium...
We feature a multi-parametric approach based on an imaging flow cytometry platform for examining phagocyte antimicrobial responses against the gram-negative bacterium Aeromonas veronii. This pathogen is known to induce strong inflammatory responses across a broad range of animal species, including humans. We examined the contribution of A. veronii to the induction of early phagocyte inflammatory processes in RAW 264.7 murine macrophages in vitro. We found that A. veronii, both in live or heat-killed forms, induced similar levels of macrophage activation based on NF-κB translocation. Although these macrophages maintained high levels of viability following heat-killed or live challenges with A. veronii, we identified inhibition of macrophage proliferation as early as 1h post in vitro challenge. The characterization of phagocytic responses showed a time-dependent increase in phagocytosis upon A. veronii challenge, which was paired with a robust induction of intracellular respiratory burst responses. Interestingly, despite the overall increase in the production of reactive oxygen species (ROS) among RAW 264.7 macrophages, we found a significant reduction in the production of ROS among the macrophage subset that had bound A. veronii. Phagocytic uptake of the pathogen further decreased ROS production levels, even beyond those of unstimulated controls. Overall, this multi-parametric imaging flow cytometry-based approach allowed for segregation of unique phagocyte sub-populations and examination of their downstream antimicrobial responses, and should contribute to improved understanding of phagocyte responses against Aeromonas and other pathogens.
Topics: Animals; Anti-Infective Agents; Cell Proliferation; Cells, Cultured; Flow Cytometry; Image Cytometry; Inflammation; Macrophage Activation; Macrophages; Mice; NF-kappa B; Phagocytes; Phagocytosis; Reactive Oxygen Species; Respiratory Burst
PubMed: 25862969
DOI: 10.1016/j.jim.2015.03.016