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PubMed2006

AM-3K, an anti-macrophage antibody, recognizes CD163, a molecule associated with an anti-inflammatory macrophage phenotype.

CD163 is a member of the scavenger receptor cysteine-rich superfamily restricted to the monocyte/macrophage lineage and is thought to be a useful marker for anti-inflammatory or alternatively activated macrophages. In this study we used mass spectrometric analysis to determine that the antigen recognized by the antibody AM-3K, which we previously generated as a tissue macrophage-specific monoclonal antibody, was CD163. An anti-inflammatory subtype of macrophages stimulated by dexamethasone or interleukin-10 showed strong reactivity for AM-3K and increased expression of CD163 mRNA. Immunohistochemical staining of routinely processed pathological specimens revealed that AM-3K recognized a specialized subpopulation of macrophages. In granulomatous diseases such as tuberculosis, sarcoidosis, or foreign body reactions, tissue macrophages around granulomas, but not component cells of the granulomas such as epithelioid cells and multinucleated giant cells, showed positive staining for AM-3K. In atherosclerotic lesions, scattered macrophages in diffuse intimal lesions were strongly positive for AM-3K, whereas foamy macrophages in atheromatous plaques demonstrated only weak staining. We therefore suggest that, in routine pathological specimens, AM-3K is a useful marker for anti-inflammatory macrophages because these cells can be distinguished from inflammatory or classically activated macrophages. Because AM-3K cross-reacts with macrophage subpopulations in different animal species including rats, guinea pigs, rabbits, cats, dogs, goats, pigs, bovine species, horses, monkeys, and cetaceans, it will have wide application for detection of CD163 in various animals.

Antigens, CD↗
PubMed2000

Role of IL-12 in macrophage activation during intracellular infection: IL-12 and mycobacteria synergistically release TNF-alpha and nitric oxide from macrophages via IFN-gamma induction.

IL-12 is believed to play an important role in cell-mediated immunity against intracellular infection primarily by acting on T and NK cells. Recent evidence has suggested, however, that IL-12 has broader cellular targets than previously thought. In this study, we examined the role of IL-12 in macrophage TNF-alpha and nitric oxide (NO) release by using an in vitro model of intracellular infection. IL-12 alone released relatively little TNF-alpha and NO, whereas live mycobacteria alone released TNF-alpha markedly but little NO from murine alveolar macrophages. However, IL-12 and mycobacteria together enhanced TNF-alpha and NO release synergistically. Because IL-12 and mycobacteria also released IFN-gamma from macrophages synergistically, and exogenous IFN-gamma with mycobacteria enhanced TNF-alpha and NO release synergistically, we examined the role of endogenous IFN-gamma in IL-12/mycobacteria-stimulated macrophage activation. Using macrophages from mice deficient in IFN-gamma, we found that IL-12/mycobacteria-enhanced macrophage TNF-alpha and NO release was mediated through endogenous IFN-gamma. We further demonstrated that IFN-gamma and mycobacteria together had a selective effect on macrophage cytokine release because they released TNF-alpha synergistically but not macrophage chemotactic protein-1 (MCP-1). These findings reveal that IL-12 can activate macrophages potently during intracellular infection, and this activating effect is mediated primarily through its effect on macrophage IFN-gamma release.

Animals↗
PubMed1989

Recombinant granulocyte-macrophage colony-stimulating factor increases adenylate cyclase activity in murine peritoneal macrophages.

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotrophic cytokine which stimulates the function and proliferation of macrophage populations. Although the effects of GM-CSF are diverse and GM-CSF has entered into clinical trials, relatively little is known about signal transduction pathways utilized by GM-CSF. In view of previous studies which have suggested that some of the effects of GM-CSF on monocyte-macrophages can be mimicked by agents which increase intracellular cAMP, we investigated the effect of rGM-CSF on adenylate cyclase (AC) activity in murine peritoneal macrophages. Adenylate cyclase activity was quantitated in macrophage membrane preparations and in intact cells. In seven separate experiments, GM-CSF (50 U/ml) increased AC activity by 61(6)% relative to macrophages treated with carrier medium alone. A dose-dependent increase in AC activity was observed (10 to 100 U/ml) which peaked within 1 to 5 min after the addition of GM-CSF and returned to basal levels by 10 to 20 min. Lineweaver-Burk analysis revealed that the Vmax of macrophage AC was increased from 0.40 to 0.52 pmoles cAMP/min by GM-CSF but the Km was unchanged. Intracellular cAMP was increased by GM-CSF to 129(27)% of control values by 1 min of treatment (n = 6). Under similar experimental conditions, GM-CSF did not increase the activity of PK C (n = 14) or phospholipase A2 (n = 3) in peritoneal macrophages. These data show that macrophage adenylate cyclase activity is rapidly stimulated by GM-CSF. Moreover, these findings support further study of the role of cAMP in transmitting the intracellular signals initiated by GM-CSF in tissue macrophages.

Adenylyl Cyclases↗
PubMed1984

Lactoferrin acts on I-A and I-E/C antigen+ subpopulations of mouse peritoneal macrophages in the absence of T lymphocytes and other cell types to inhibit production of granulocyte-macrophage colony stimulatory factors in vitro.

The relationship between Ia antigens on mouse resident peritoneal macrophages and the ability of lactoferrin (LF) to inhibit the production of granulocyte-macrophage colony stimulatory factors (GM-CSF) from these cells was investigated. Detection of the suppressive influence of LF on release of GM-CSF from greater than or equal to 10(5) macrophages/ml/plate required that the conditioned media being assessed for GM-CSF be prepared in the presence of indomethacin and/or be preincubated with anti-ferritin antiserum to respectively stop production of E-type prostaglandins and to remove acidic isoferritin-inhibitory activities that can mask the effects of LF. Treatment of mouse macrophages with monoclonal antibodies to the I-A and I-E/C subregions of Ia antigens in a complement C-dependent cytotoxicity assay killed less than 15% of the cells, but removed all Ia antigen+ macrophages and reduced GM-CSF production by approximately 50%. LF decreased GM-CSF production by untreated macrophages by approximately 50%, but had no effect on macrophages insensitive to treatment with anti-Ia plus C. Macrophages left at 37 degrees C for 5 and 24 hr were not killed by treatment with monoclonal anti-Ia plus C and GM-CSF production by these macrophages was not suppressed by LF. Treatment of macrophages with monoclonal anti-H-2K or anti-Mac-1 plus C reduced GM-CSF production greater than 95%. Anti-I-A, -I-E/C, -H-2K, or -Mac-1, in the absence of C, had no effect on viability of macrophages or on production of GM-CSF, but anti-I-A and -I-E/C each blocked the inhibitory action of LF. Lower concentrations of these antibodies could block the action of LF when anti-I-A and anti-I-E/C were mixed together better than when they were each used separately. The removal of Thy-1.2+ cells from unseparated or adherent peritoneal cells resulted in populations of cells that were up to 100% positive for nonspecific esterase, and did not influence GM-CSF production from these cells, the reduction of GM-CSF from these cells by LF, or the reduction of GM-CSF by the removal of Ia antigen+ cells. The results were similar whether or not T cells were removed from the assay marrow by treatment with antibodies Ly-1.1, Ly-2.2, and Qa4 plus C.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

T cell-macrophage cognate interaction in the activation of macrophage effector function by Th2 cells.

The in vitro induction of cytostatic/cytotoxic activity in macrophages generated in spleen cell cultures requires a signal cascade initiated by costimulation with both LPS and IFN-gamma. Th2 lymphocytes, although they do not produce IFN-gamma, can provide the signals necessary for induction of cytostatic activity in IFN-gamma-primed macrophages. These signals appear to be delivered by cognate interaction between the Th2 cells and macrophages in that: 1) they are not delivered by culture supernatants of Th2 cells activated 6 or 20 h by Con A or by immobilized anti-CD3 mAb; 2) they are not delivered if cell contact between Th2 cells and macrophages is prevented; and 3) they can be delivered by paraformaldehyde-fixed activated Th2 cells. Paraformaldehyde-fixed resting Th2 cells cannot stimulate activation of INF-gamma-primed macrophages. The Th2 cells must be activated at least 3 h before fixation to acquire macrophage stimulatory activity. Optimal macrophage-stimulating activity is attained after 6-h activation of the Th2 and declines thereafter. Although the activation of IFN-gamma-primed macrophages by viable resting Th2 displays Ag specificity and MHC restriction, the activation of IFN-gamma-primed macrophages by paraformaldehyde-fixed activated Th2 is neither Ag specific nor MHC restricted. These observations suggest that T cell-mediated activation of macrophages can involve a signaling cascade of Ag-specific and Ag-nonspecific adhesion events comparable to those hypothesized to occur in T cell-mediated B cell activation.

Animals↗
PubMedDate not supplied

Analysis of Egr-1 protein induction in murine peritoneal macrophages treated with granulocyte-macrophage colony-stimulating factor.

Transcription of early growth response gene-1 (Egr-1) is required for macrophage differentiation. Since granulocyte-macrophage colony-stimulating factor (GM-CSF) induces macrophage proliferation as well as the transcription of Egr-1 mRNA, we characterized the induction of Egr-1 protein in murine peritoneal macrophages following treatment with GM-CSF. As determined by Western blot analysis, the concentration of GM-CSF required to induce detectable Egr-1 protein in macrophages was 50 units/ml, and the inducible Egr-1 protein species was 80 kDa. Following stimulation of macrophages with GM-CSF, Egr-1 protein was detected within 25 min and reached maximum level at 70 min. The concentration of GM-CSF that was required to induce Egr-1 protein in macrophages was similar to that required to induce macrophage proliferation. A similar concentration has been detected previously in mouse serum exposed to bacterial endotoxin in vivo, suggesting that the 80 kDa Egr-1 protein may be induced in macrophages under the physiologic circumstances of pathogen invasion. Thus, our data support further study on the role of Egr-1 protein in mediating GM-CSF induction of macrophage proliferation.

Animals↗
PubMed1980

Cytolytic activity against tumor cells by macrophage cell lines and augmentation by macrophage stimulants.

Previous studies have shown that macrophage cell lines retained the ability to phagocytize, to secrete lysosomal enzymes, and to function as effector cells in antibody-dependent cellular cytoxicity. In this paper, the cytolytic activity of murine macrophage cell lines against tumor target cells was assessed using an 18-h 51Cr release assay. Of the macrophage cell lines tested, RAW 264, PU5-1.8 and IC-21 had intermediate to high levels of spontaneous cytolytic activity, P388D, and J774 had low to intermediate levels, while /WEHI-3 showed little or no cytolytic activity against RBL-5, MBL-2 and TU-5 target cells. Tumor-cell killing by macrophage cell lines could be augmented by the addition of macrophage stimulants, such as bacterial lipopolysaccharide and poly I:C, indicating that the activation of macrophages by these stimulants does not require the participation of other cell types. Treatment with interferon also augmented the tumor-cell killing by macrophage cell lines. Although the mechanism by which these cell lines exert their spontaneous or boosted cytotoxic activity is not clear, it does not appear to be due to depletion of nutrients since cell lines with high metabolic and proliferative activities, such as WEHI-3 and RBL-5, showed little or no cytotoxicity and supernatants from the macrophage cell lines did not exert any cytotoxic effects in their essay. Thus, it appears that the different macrophage cell lines represent different levels of activation and/or differentiation and may be useful for studying the development of these processes as well as providing a useful tool for analyzing the mechanisms of macrophage-mediated cytolysis.

Adjuvants, Immunologic↗
PubMed2002

Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy.

Large numbers of monocytes extravasate from the blood into human tumours, where they differentiate into macrophages. In both breast and prostate carcinomas, these cells accumulate in areas of low oxygen tension (hypoxia), where they respond to hypoxia with the up-regulation of one or more hypoxia-inducible factors (HIFs). These then accumulate in the nucleus and bind to short DNA sequences called hypoxia-response elements (HREs) near or in such oxygen-sensitive genes as that encoding the pro-angiogenic factor vascular endothelial growth factor (VEGF). This stimulates gene expression and could explain why, in part, macrophages express abundant VEGF only in avascular, hypoxic areas of breast carcinomas. It also suggests that macrophages could be used to deliver HRE-regulated therapeutic genes specifically to hypoxic tumour areas. A recent study suggested that hypoxic macrophages accumulate HIF-2 rather than HIF-1, prompting the search for HRE constructs that optimally bind HIF-2 for use in macrophage-based gene therapy protocols. However, the present study shows that human macrophages accumulate higher levels of HIF-1 than HIF-2 when exposed to tumour-specific levels of hypoxia in vitro; that macrophages in human tumours express abundant HIF-1; and that expression from HRE-driven reporter constructs in the human macrophage-like cell line MonoMac 6 correlates more closely with HIF-1 than with HIF-2 up-regulation under hypoxia. Taken together, these findings suggest that HIF-1 may be the major hypoxia-inducible transcription factor in macrophages and that HIF-1-regulated constructs are likely to be effective in macrophage delivery of hypoxia-regulated gene therapy to human tumours.

Antigens, CD↗
PubMed2004

C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases.

Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2-/-) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 -/- mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2-/- and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2-/- mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2-/- mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2-/- mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2-/- mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2-/- mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production.

Animals↗
PubMed1994

Ultrastructural localization of tissue factor on monocyte-derived macrophages and macrophage foam cells associated with atherosclerotic lesions.

The expression of tissue factor (TF) antigen by circulating monocytes, cultured macrophages, and macrophages associated with atherosclerotic lesions was ultrastructurally analysed using immunogold labeling. A subpopulation of macrophages associated with the intimal surface overlying lesions had a significant TF expression. Macrophages and macrophage foam cells that projected from the intima into the arterial lumen also expressed a high level of TF (14-fold increase over control). In contrast, circulating monocytes and macrophages in culture did not express TF above background control levels. This TF expression by macrophages in vivo but not by macrophages cultured from either normal or hypercholesterolemic animals suggests that monocyte activation and macrophage transition, as measured by TF expression, is lesion-dependent and not stimulated solely by intimal attachment, surface migration, or hypercholesterolemia. These results further suggest that macrophages and foam cells associated with early lesions of atherosclerosis can initiate fibrin formation, which could contribute to lesion complications and transition to a fibromuscular stage.

Animals↗
PubMed1980

Proliferation activity and bacteriostatic potential of human blood monocytes, macrophages in pleural effusions, ascites, and of alveolar macrophages.

Human blood monocytes, macrophages from pleural effusions, ascites, and alveolar macrophages obtained by bronchopulmonary lavage were investigated. The proliferative activity of these cells was determined by the 3H-thymidine labeling index in vitro (3H-TDR L.I.). The bacteriostatic capacity was measured by the potential of the cells to block DNA-synthesis of proliferating Escherichia coli after phagocytosis. In most cases 3H-TDR L.I. of blood monocytes, macrophages from pleural effusions and ascites was less than 1%. However, macrophages of some patients with neoplastic diseases exhibited 3H-TDR L.I. between 4.0--9.6%. This probably reflected the action of factors, possibly lymphokines, which stimulated macrophage proliferation. In contrast, alveolar macrophages seemed to have almost totally lost their proliferative potential. The bacteriostatic capacity of blood monocytes proved to be significantly lower than that of macrophages. This demonstrates the functional immaturity of blood monocytes. In all type of macrophages investigated the bacteriostatic power was very high. No differences could be detected either between macrophages of different sources or between macrophages of benign, inflammatory, or malignant diseases.

Ascites↗
PubMed1986

Stimulatory effects of purified macrophage colony-stimulating factor on murine resident peritoneal macrophages.

A purified preparation of macrophage colony-stimulating factor (M-CSF) free of interferon and endotoxin activity was studied for its effects on resident murine peritoneal macrophages. M-CSF was found to induce profound morphologic alterations in resident macrophages. These changes included a marked increase in cell size, membrane ruffling, and cytoplasmic vacuolization. Further, after 72 hr of incubation with 1000 U/ml of M-CSF, there were significant increases in macrophage DNA synthesis as measured by autoradiography (P less than 0.001), and in macrophage monolayer protein content (P less than 0.01). None of these changes was seen in control macrophages or those exposed to recombinant interferon-gamma (IFN). Low activity levels of the ectoenzymes 5'-nucleotidase (5'NTD) and alkaline phosphodiesterase I (APD) have been associated with certain macrophage functions, particularly the expression of tumor cytotoxicity. Macrophage monolayers exposed to M-CSF demonstrated an unaltered level of 5'NTD activity from controls and a significantly increased level of APD activity (P less than 0.01) and did not demonstrate an increased ability to kill tumor cells, as measured by the 51Cr-release assay. On the other hand, IFN caused significant decreases in both 5'NTD (P less than 0.05) and APD (P less than 0.01) and also induced marked tumoricidal activity in macrophage monolayers. These results indicate that purified M-CSF induces highly specific alterations in the functional activity and morphologic appearance of resident macrophages and these changes are distinct from those induced by IFN.

5'-Nucleotidase↗
PubMed1992

The effect of liver macrophages on in vitro cytolytic activity of 5FU and FUdR on colon carcinoma cells: evidence of macrophage activation.

While investigating the effects of 5-fluorouracil (5FU) and 5-fluoro-2'-deoxyuridine (FUdR) on the tumoricidal state of rat liver macrophages activated in vitro by means of liposome-encapsulated muramyl dipeptide (MDP), we observed that 5FU in combination with macrophages produced substantially higher extents of cytolytic activity on tumor cells than 5FU alone. In contrast, FUdR failed to produce this effect; rather, at relatively low FUdR concentrations, lytic activity in the presence of macrophages was even significantly diminished as compared with FUdR in the absence of macrophages. Both 5FU and FUdR were able to enhance the cytolytic activity of macrophages activated by liposome-encapsulated MDP. This finding indicates that, rather than inhibiting the activation of macrophages by liposomal MDP, 5FU can act as a stimulator of macrophage activation by itself. This is further supported by the observations that (i) in combination with 5FU, the secretion of TNF induced by liposomal MDP was synergistically enhanced and (ii) that a second treatment of macrophages with the drug, 24 h after the first, fails to produce increased macrophage cytotoxicity. Our results also show that neither 5FU nor FUdR are likely to unfavorably influence the induction of cytotoxic activity of the macrophages. Rather, combinations of 5FU or FUdR and liposomal MDP may result in an additive or synergistic tumoricidal effect.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Changing pattern of the subcellular distribution of erythroblast macrophage protein (Emp) during macrophage differentiation.

Erythroblast macrophage protein (Emp) mediates the attachment of erythroid cells to macrophages and is required for normal differentiation of both cell lineages. In erythroid cells, Emp is believed to be involved in nuclear extrusion, however, its role in macrophage differentiation is unknown. Information on the changes in the expression level and subcellular distribution of Emp in differentiating macrophages is essential for understanding the function of Emp. Macrophages of varying maturity were examined by immunofluorescence microscopy and biochemical methods. Our data show that Emp is expressed in all stages of maturation, but its localization pattern changes dramatically during maturation: in immature macrophages, a substantial fraction of Emp is associated with the nuclear matrix, whereas in more mature cells, Emp is expressed largely at cell surface. Pulse-chase experiments show that nascent Emp migrates intracellularly from the cytoplasm to the plasma membrane more efficiently in mature macrophages than in immature cells. Incubation of erythroid cells with macrophages in culture shows that erythroid cells attach to mature macrophages but not to immature macrophage precursors. Together, our data show that the temporal and spatial expression of Emp correlates with its role in erythroblastic island formation and suggest that Emp may be involved in multiple cellular functions.

Animals↗
PubMed2000

Identification of macrophages at the site of peritoneal injury: evidence supporting a direct role for peritoneal macrophages in healing injured peritoneum.

OBJECTIVE: To determine if peritoneal macrophages are present at the site of a surgical injury to the peritoneum during wound healing. DESIGN: Controlled research study. SETTING: Academic research laboratory. EXPERIMENTAL MODEL: A murine model of peritoneal wound healing. INTERVENTION(S): Intraperitoneal injection of polystyrene beads 1 hour after a surgical peritoneal injury to identify peritoneal macrophages. MAIN OUTCOME MEASURE(S): Presence of peritoneal macrophages at the site of the healing wound as determined by intracellular polystyrene beads on transmission electron microscopy 1, 3, 7, and 14 days after injury. RESULT(S): Peritoneal macrophages were easily distinguished from other cell types by the phagocytosis of polystyrene beads. One day after injury, peritoneal macrophages were adherent to the wound surface. By 3 days, mesothelial cells began covering the peritoneal macrophages at the wound surface and peritoneal macrophages were identified deep within the wound. Seven days after injury, the mesothelial layer was completely reconstituted, but peritoneal macrophages persisted within the healing would below the surface mesothelium. CONCLUSION(S): These data indicate that peritoneal macrophages are present at the peritoneal injury site throughout the healing interval and are consistent with these macrophages having a critical role in peritoneal wound healing.

Animals↗
PubMed1985

Characterization of pulmonary macrophages and bronchus-associated lymphoid tissue (BALT) macrophages in the rat. An enzyme-cytochemical and immunocytochemical study.

Three subpopulations of macrophages present in the lung, viz. pulmonary alveolar macrophages (PAM), pulmonary tissue macrophages (PTM), and macrophages in the bronchus-associated lymphoid tissue (BALT), were compared using enzyme-cytochemical and immunocytochemical methods. BALT macrophages can be distinguished from PAM and PTM on the basis of their enzyme reaction products. With three monoclonal antibodies, ED1, ED2, and ED3, that recognize different antigen determinants of rat macrophages, the three subpopulations could be clearly distinguished. PAM are ED1-positive and PTM are ED2-positive. The macrophage subpopulation scattered throughout BALT is ED1-positive; macrophages situated at the peripheral site of BALT, near artery and bronchus, are ED2-positive. No ED3-positive macrophages were observed either in the lung or in BALT. These results are discussed with respect to the possible relationship between the subpopulations of pulmonary macrophages.

5'-Nucleotidase↗
PubMedDate not supplied

Effect of sensitized macrophages in transplantable sarcoma in mice. synergistic effect of hyperimmunized serum, sensitized spleen cells and macrophages in tumor transplantation.

BACKGROUND: Immunosuppression cannot develop tumors by itself. It may induce tumors under appropriate conditions and may accelerate tumor development which may be reversed by sensitized spleen cells. This study concerns the effect of sensitized macrophages in murine-transplantable sarcomas by a combination of hyperimmune serum, sensitized spleen cells and macrophages. METHODS: The main technique adopted was intraperitoneal (ip) injection of 2 mL of 10% protease peptone broth, followed 2 days later by inoculation into the peritoneum with 10-mL Hank isotonic solution. The cells from the pooled peritoneal fluid were tested by dye exclusion test to ascertain the percentage of live cells. They were tried in whole body-irradiated mice with a combination of immune serum and sensitized spleen cells to ascertain whether a suppression of growth of solid tumors could be achieved when subcutaneously (sc) administered with the previously mentioned combinations. RESULTS: The addition of immunomacrophages from transplanted tumor-bearing mice significantly suppressed the growth of subcutaneous solid tumors when the number of tumor cells was kept constant. A change in number of immunomacrophages from hyperimmunized mice at a ratio of 4:l showed a direct relationship in suppression of tumor growth. Experiments were initiated in which tumor cells were injected sc and peritoneal macrophages were injected either intravenously (iv) or ip. Experiments were then initiated to prove that cell-to-cell contact is essential for tumor suppression. In experiments in which tumor cells were administered sc and macrophages injected either iv or ip, a significant immunosuppressive effect was not shown, thus also indicating that regardless of which, cell-to-cell contact is an absolutely essential factor involved in tumor suppression. A combination of hyperimmune serum and macrophages was found to act synergistically. Macrophages and hyperimmune serum at a lesser proportion did not suppress tumor growth. Sensitized macrophages and spleen cells together significantly suppressed tumor growth in a pure isogenic strain of irradiated mice. The sensitized macrophages injected iv prolonged the survival period and retarded tumor growth. CONCLUSIONS: Tumor suppression by macrophages was found to be due to its contact with tumor cells that enables the effective transfer of immunity. Hyperimmune serum and other cells (macrophages, spleen lymphocytes) act synergistically toward each other and prolong the survival period.

Animals↗
PubMed1980

Macrophage microbicidal activity. Correlation between phagocytosis-associated oxidative metabolism and the killing of Candida by macrophages.

The mechanisms by which macrophages kill ingested microorganisms were explored using Candida albicans and Candida parapsilosis. The results indicate that efficient macrophage candidacidal activity depends upon the generation of oxygen metabolites by the phagocytic cell: (a) peritoneal macrophages from mice infected with bacillus Calmette-Guerin (BCG) or injected intraperitoneally with lipopolysaccharide (LPS) released more superoxide anion (0(2)(-)) during phagocytosis of candida and killed candida better than did resident macrophages; (b) cells of the macrophage-like line J774.1, which released negligible amounts of O(2)(-), could ingest the candida normally but not kill them; (c) killing of candida by resident, LPS- elicited, and BCG-activated macrophages was inhibited by agents that scavenge O(2)(-), hydrogen peroxide (H(2)0(2)), hydroxyl radical (x OH), and singlet oxygen; and (d) all three macrophage types killed C. parapsilosis more effectively than C. albicans, and (7. parapsilosis stimulated a more prompt and vigorous burst of macrophage oxygen consumption and 0(2)(-) release than did C. albicans. Macrophages ingested C. parapsilosis slightly more quickly than C. albicans, but phagocytosis of both strains was equivalent by 60 min of incubation. Although C. albicans contained higher concentrations of the oxygen-metabolite scavengers superoxide dismutase and catalase, neither fungal species scavenged 0(2)(-) or H(2)0(2) effectively; and C. albicans was killed more easily than C. parapsilosis by a xanthine oxidase system that generates primarily H(2)O(2) at pH 7, or 0(2)(-) and x OH at pH 10. Thus, the decreased killing of C. albicans appears to result primarily from the capability of this species to elicit less vigorous stimulation of macrophage oxidative metabolism. This capability may have general relevance to the pathogenicity of microorganisms.

Animals↗