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M S Meltzer

Publications and source records attributed to M S Meltzer.

At least 127 records · Page 7Linked to original sources
PubMed1982

Macrophages as effector cells of protective immunity in murine schistosomiasis. II. Killing of newly transformed schistosomula in vitro by macrophages activated as a consequence of Schistosoma mansoni infection.

Plastic adherent peritoneal cells from Schistosoma mansoni-infected mice have previously been shown to exhibit nonspecific tumoricidal activity in vitro. In this report we show that these same cell populations kill significant numbers of skin-stage schistosomula in vitro in the absence of added antibody. Larval killing by these activated cells could be enhanced by the use of suspension rather than monolayer cultures and by addition of heat-inactivated immune mouse serum to the cultures. Adherence of cells to schistosomula was also enhanced under the same conditions, suggesting that cell binding to the larvae might be critical in the development or expression of microbicidal activity. In support of this hypothesis, the same level of enhancement of cell binding and larval damage was observed upon substitution of concanavalin A for immune mouse serum. Killing of schistosomula appeared to be mediated solely by activated macrophages in the peritoneal cell suspensions from S. mansoni-infected mice, because partially purified preparations of eosinophils were virtually inactive in these assays. Likewise, inflammatory macrophages from uninfected mice were unable to kill schistosomula under the same conditions, emphasizing the importance of activation in the development of killing capability. The finding that macrophages activated as a consequence of S. mansoni infection are able to kill larval schistosomes in vitro suggests that these cells may play a role in concomitant immunity to schistosomiasis in vivo.

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PubMed1982

Macrophages as effector cells of protective immunity in murine schistosomiasis. III. Loss of susceptibility to macrophage-mediated killing during maturation of S. mansoni schistosomula from the skin to the lung stage.

Newly transformed skin-stage and lung-stage schistosomula were compared in terms of their susceptibility to killing mediated by activated mouse macrophages in vitro. Although skin-stage schistosomula were readily killed by macrophages activated as a consequence of either BCG or Schistosoma mansoni infection and used either as cell monolayers or in suspension, lung-stage larvae appeared to be totally resistant to this effector mechanism and survived normally when reinjected into mice. Resistance of schistosomula to in vitro damage by macrophages was evident as early as 18 hr after host infection and was complete in worms recovered at 42 hr. The insusceptibility of lung-stage larvae is apparently not due to a defect in effector cell-target contact, because the induction of extensive macrophage adherence to the worms by the addition of anti-mouse red blood cell antisera to the cultures had no effect on parasite viability. These findings provide additional support for the concept that schistosomula during their development to the lung stage undergo a generalized change affecting their susceptibility to a variety of different immunologic effector mechanisms.

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PubMed1982

Macrophage activation for tumor cytotoxicity: regulatory mechanisms for induction and control of cytotoxic activity.

Macrophage activation for nonspecific tumor cytotoxicity occurs after completion of a series of reactions, each of which requires the simultaneous presence of effective activation signals and competent mononuclear phagocytes. This reaction sequence can be conceptually divided into three phases: precursor differentiation, priming, and trigger reactions, The first phase involves recruitment and differentiation of immature, blood-derived mononuclear phagocytes into competent, lymphokine-responsive cells by factors generated at the site of inflammation. Complete expression of nonspecific effector function by activated macrophages occurs after two additional phases: inflammatory macrophages first respond to certain lymphokine signals and enter into a receptive or primed state in which they are not yet cytotoxic, but can then respond or be triggered by other signals to develop full functional activity. These lymphokine-priming and trigger signals form the basis of a regulatory system that sets the threshold and determines the onset of macrophage effector activity.

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PubMed1981

Inhibition of nonspecific tumoricidal activity by activated macrophages with antiserum against a soluble cytotoxic factor.

Mouse peritoneal macrophages activated for tumor cytotoxicity by any of several in vivo or in vitro treatments released a soluble cytotoxin into culture fluids only after exposure to small amounts of bacterial lipopolysaccharides. This cytotoxic factor was physicochemically similar to the cytotoxic factor (tumor necrosis factor) in sera of BCG-infected mice injected with lipopolysaccharide. A rabbit antiserum against partially purified serum cytotoxic factor also inhibited the activity of macrophage-derived cytotoxic factor. Of special interest was the observation that rabbit anti-cytotoxic factor inhibited the cytotoxic activity of macrophages both in the presence and in the absence of exogenously added lipopolysaccharide. Inhibition was not complete but was consistent in all experiments. Thus, cytotoxic factor was implicated as a possible effector molecule in the nonspecific tumoricidal activity of activated macrophages.

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PubMed1981

Characterization of genetic defects in macrophage tumoricidal capacity: identification of murine strains with abnormalities in secretion of cytolytic factors and ability to bind neoplastic targets.

Peritoneal macrophages from BCG-infected C3H/HeJ or A/J mice, in contrast to BCG-activated macrophages from C3H/HeN mice, were ineffective at lysing adherent 1023 sarcoma targets, nonadherent P815 mastocytoma targets, or nonadherent EL-4 lymphoma targets. The ability of macrophages from BCG-infected C3H/HeJ mice to secret cytolytic factor (CF) into the supernatant medium was markedly impaired. This secretory deficit, however, did not extend to plasminogen activator, secretion of which was augmented. In contrast, the ability of BCG macrophages from A/J mice to secrete CF was comparable to or even slightly higher than that of macrophages from C3H/HeN mice. The ability of BCG-elicited macrophages from A/J mice to bind either of 2 neoplastic targets (the P815 mastocytoma and the EL-4 lymphoma), however, was greatly reduced. The ability of BCG-elicited macrophages from C3H/HeJ mice to bind these targets was comparable to that of macrophages from C3H/HeN mice. The data suggest that the phenotypically-similar deficits in tumoricidal capacity of BCG-elicited macrophages from C3H/HeJ and A/J mice are mediated by mechanistically different defects in macrophage-tumor cell interactions.

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PubMed1981

Macrophages in resistance to rickettsial infections: characterization of lymphokines that induce rickettsiacidal activity in macrophages.

Lymphokine-rich culture supernatants of antigen- or mitogen-stimulated spleen cells were fractionated by Sephadex G-200 column chromatography; fractions were assayed for capacity to induce tumoricidal and rickettsiacidal activities in mouse macrophages. Lymphokine activity that activated macrophages for tumor cytotoxicity eluted as a single peak in the 45,000 m.w. region. In contrast, activity for intracellular killing of rickettsiae eluted in 3 distinct regions: 115 to 125,000, 35 to 45,000, and less than 10,000 daltons. This elution pattern was observed with both antigen and mitogen-induced lymphokines. Activity of each of the 3 lymphokine species for induction of rickettsiacidal activity was destroyed by heating at 56 degrees C for 1 hr. Tumor cytotoxicity and rickettsiacidal activity, both effector functions of activated macrophages, were dissociated on the basis of lymphokines regulating these activities.

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PubMed1981

The ADCC capacity of macrophages from C3H/HeJ and A/J mice can be augmented by BCG.

Macrophages elicited from the peritoneal cavity of C3H/HejJ and A/J mice by bacillus Calmette-Guérin (BCG), although ineffective in mediating tumor cytotoxicity, had augmented capacity to mediate antibody-dependent cellular cytotoxicity (ADCC) against both erythroid and neoplastic target cells. The level of augmented ADCC was comparable to that expressed by BCG-activated macrophages from control C3H/HeN mice. The data suggest that the defective potential for cytolytic activation in 2 genetically deficient strains of inbred mice does not extend to augmentation of capacity for mediating ADCC and that full expression of cytolytic activation is not necessary for expression of augmented cytolysis of antibody-coated targets.

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PubMed1981

Intracellular replication and lymphokine-induced destruction of Leishmania tropica in C3H/HeN mouse macrophages.

C3H/HeN resident peritoneal macrophages in suspension culture supported continuous replication of L. tropica amastigotes; the total number of intracellular parasites increased 8- to 10-fold over 96 hr in culture. Lymphokine treatment of macrophages markedly affected intracellular replication of the Leishmania. Cultures treated with lymphokines before exposure to L. tropica were more resistant to infection, and 35% fewer cells contained intracellular amastigotes compared to medium-treated controls. Lymphokine-pretreated cells that became infected also inhibited the replication of intracellular amastigotes. Macrophage cultures treated with lymphokines after infection exhibited potent microbicidal activity; 75 to 80% of macrophages were free of intracellular parasites by 72 hr. Fractionation of lymphokine supernatants by Sephadex G-100 demonstrated 3 areas of activity for the induction of macrophage intracellular killing (130,000, 45,000, less than or equal to 10,000 daltons); one of these activity peaks (45,000-m.w. lymphokine(s)) also induced increased resistance to infection with L. tropica.

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PubMed1980

Generation and characterization of a lipopolysaccharide-induced and serum-derived cytotoxic factor for tumor cells.

Serum from Mycobacterium bovis BCG-infected mice treated with lipopolysaccharide was cytotoxic to tumor cells in vitro. Serum-induced cytotoxicity was estimated by measuring release of [3H]thymidine into culture supernatants of prelabeled tumor target cells. Serum from BCG-infected mice not treated with lipopolysaccharide or from uninfected mice treated with lipopolysaccharide was inactive. Moreover, although serum cytotoxic activity was evident with 10 syngeneic or allogeneic tumor cell lines, little or no effect was observed with normal embryonic fibroblast target cells. Maximal titers of serum cytotoxic activity were detected 14 days after BCG infection and 2 h after LPS treatment. Serum of BCT-infected, T-cell-deficient nude mice developed strong cytotoxic activity after LPS treatment; however, lipopolysaccharide-insensitive C3H/HeJ mice could produce this cytotoxic activity only after adoptive transfer with lipopolysaccharide-responsive C3H/HeN bone marrow. Physicochemical characterization of the serum cytotoxic activity revealed a heat-stable (56 degrees C, 30 min) entity with a molecular weight of about 60,000 and an isoelectric point at pH 4.8. Biological and physicochemical characteristics of this serum cytotoxic activity as defined by an in vitro assay were very similar to characteristics of tumor necrosis factor and suggest that this molecule may be a major effector mechanism for the antitumor actions of lipopolysaccharide.

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PubMed1980

Defective tumoricidal capacity of macrophages from P/J mice: characterization of the macrophage cytotoxic defect after in vivo and in vitro activation stimuli.

Unlike macrophages from responsive mouse strains, peritoneal cells of P/J mice treated in vivo with viable Mycobacterium bovis, strain BCG, or killed Corynebacterium parvum fail to develop tumoricidal activity. P/J macrophages treated in vitro with lymphokine-rich supernatants, bacterial endotoxic lipopolysaccharides (LPS) or T cell mitogens also fail to develop cytotoxic activity. Experimental manipulation of effector:target cell ratios, doses of activation stimuli, or tumor target cells did not evoke cytotoxic activity. The macrophage defect of P/J mice appeared similar to that of lipid A-insensitive C3H/HeJ mice. The macrophage defect of C3H/HeJ mice is controlled by a gene identical or closely linked to the Lpsd gene. Tumoricidal defects of P/J macrophages, however, appeared independent of the Lpsd gene: responses of P/J spleen cells or macrophages to LPS, which are controlled by the Lps gene, were normal. P/J mice therefore represent a distinct and potentially useful genetic probe for characterization of mechanisms in macrophage activation.

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