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C Cheers

Publications and source records attributed to C Cheers.

At least 37 records · Page 2Linked to original sources
PubMed1995

Endogenous interleukin-12 is involved in resistance to Brucella abortus infection.

Protective immunity against Brucella abortus is mediated by acquired cellular resistance, with gamma interferon (IFN-gamma)-producing T cells playing a key role. Interleukin-12 (IL-12) is a cytokine that has a profound effect on the induction of IFN-gamma-producing Th1 and NK cells. Here we report that depletion of endogenous IL-12 before infection of mice significantly exacerbated brucella infection. IL-12-depleted mice also had reduced splenomegaly resulting from infection and showed a decrease in percentage and absolute numbers of macrophages compared with those in control infected mice. Furthermore, spleen cells from IL-12-depleted mice had a reduced ability to produce nitrite, a product of activated macrophages. This could be the result of the low production of IFN-gamma by splenic T cells observed in the IL-12-depleted mice. The mechanism whereby IL-12 controls antibacterial resistance is discussed.

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PubMed1995

Inflammatory response following intranasal infection with Mycobacterium avium complex: role of T-cell subsets and gamma interferon.

The role of CD4+ and CD8+ T cells in the response to intranasal infection with a Mycobacterium avium complex isolate (MAC) was investigated. Depletion of CD4+ T cells by injected antibody exacerbated infection in the lung, spleen, and liver. There were decreased numbers of inflammatory cells in the lungs of CD4-depleted mice and a significant decrease in lung cytotoxic activity. The neutrophil response was unaffected, and in CD4-depleted mice, unlike intact infected mice, these cells were found with large numbers of associated MAC. Purified CD4+ splenic T cells produced gamma interferon (IFN-gamma) in vitro in response to MAC antigen. IFN-gamma production by cultured spleen, lung, or mediastinal lymph node cells was markedly reduced in CD4-depleted mice. In contrast, CD8+ T cells did not produce IFN-gamma in vitro, and depletion of CD8+ T cells from infected mice had no effect on bacterial growth or lung cell activation. Depletion of IFN-gamma by injected monoclonal antibody had effects similar to those of CD4 depletion, namely, exacerbation of infection and decreased lung cell cytotoxicity. We conclude that CD4+ T cells are the main T cells involved in the lung response to MAC infection and that this response is at least partially dependent on the production of IFN-gamma.

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PubMed1995

Role of interleukin-6 in T-cell activation during primary and secondary infection with Listeria monocytogenes.

Injection of recombinant interleukin-6 (IL-6) into mice enhances recovery from infection with Listeria monocytogenes. In this study, the role of IL-6 during primary and secondary Listeria infection was further tested. Neutralization of IL-6 by polyclonal antibody exacerbated primary infection and significantly delayed gamma interferon production by cultured spleen cells. In contrast, administration of anti-IL-6 antibody at the time of secondary infection did not affect the recovery of mice from infection or gamma interferon production, showing that activated T cells are not dependent on IL-6.

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PubMed1995

Interaction of interleukin-6, tumour necrosis factor and interleukin-1 during Listeria infection.

Injected recombinant interleukin-6 (IL-6), tumour necrosis factor (TNF) and IL-1 all protect mice against experimental infection with Listeria monocytogenes. We have therefore investigated the interaction of these cytokines during infection. Treatment with recombinant (r)IL-6 enhanced TNF production by spleen cells during the first 2 days of infection. Anti-TNF antibody could totally abolish the protective effect of rIL-6, while the optimal protective function of TNF could not be achieved when IL-6 was neutralized by anti-IL-6 antibody. IL-1 induced a high level of IL-6 in the serum a short time after its administration, and neutralization of IL-6 totally abolished the protective function of rIL-1. The results thus provide further evidence for the complexity of cytokine interaction.

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PubMed1994

Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization.

Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G-CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G-CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF-/- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during "steady-state" granulopoiesis in vivo and also implicate G-CSF in "emergency" granulopoiesis during infections.

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PubMed1994

Role of IL-6 in activation of T cells for acquired cellular resistance to Listeria monocytogenes.

We have previously shown that IL-6 is a major cytokine in the serum of mice infected with the intracellular bacterium Listeria monocytogenes, and that injection of rIL-6 before, but not after, infection promotes the recovery of mice from listeriosis. Here we demonstrate that IL-6 is required in the early stages of infection, in that injection of anti-IL-6 Ab 24 or 4 h before infection, but not 24 h after, led to a massive increase in bacterial numbers 4 or more days after infection. On the other hand, injection of rIL-6 before infection significantly suppressed bacterial numbers in the liver and spleen 3 to 4 days after infection and increased the production of IFN-gamma by in vitro cultured CD4+ and CD8+ T cells in response to specific Ag. rIL-6 did not protect SCID mice, which lack both T and B lymphocytes, against Listeria infection. The protective effect of rIL-6 was neutralized by the injection of Ab to IFN-gamma. We conclude that IL-6 plays an essential role in the activation of T cells to produce IFN-gamma, the cytokine that is central to acquired cellular resistance to intracellular bacteria.

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PubMed1994

Measurement of cellular microbicidal activity against Pneumocystis carinii in vitro.

As Pneumocystis carinii cysts cannot be cultivated for enumeration of colony forming cells, two alternative approaches to measuring killing of P. carinii by mouse peritoneal cells were investigated. The cells tested were either normal resident peritoneal cells, or cells which were elicited by intraperitoneal injection of the bacterium Listeria monocytogenes. The latter population showed enhanced antibacterial activity against Listeria organisms and enhanced production of H2O2 in the presence of P. carinii, cysts from immunosuppressed rats. To assess killing of P. carinii, cysts were mixed with peritoneal cells at a ratio of 10:1, and after intervals of incubation the peritoneal cells were lysed by saponin treatment. The viability of the cysts was assessed by staining with vital dyes or by uptake of tritiated uridine over 7 h incubation. Viability of cysts was unaffected by saponin treatment, and there was agreement between the two techniques that the elicited peritoneal cells killed approximately twice the number of cysts over a 20 h incubation period compared to normal resident peritoneal cells.

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PubMed1993

Interleukin-6 production during chronic experimental infection.

The appearance of interleukin-6 (IL-6) in serum of mice was monitored during the course of chronic infection with either Brucella abortus vaccine strain 19 or a virulent Mycobacterium avium Complex (MAC) isolate. Serum IL-6 during brucella infection was higher than during infection with MAC, despite similar numbers of bacteria. Furthermore, IL-6 titres decreased after the peak of infection, falling to baseline levels before these chronic infections were eradicated. The ability of peritoneal cells or spleen cell suspensions to produce IL-6 under either specific or non-specific stimulus was greatly enhanced by infection. While production of IL-6 by these cultures was apparently mostly independent of T cells, T cells from infected mice could produce an IL-6 response. Thus CD4+ T lymphocytes prepared from mice which had recovered from B. abortus infection, cultured with antigen and antigen presenting cells, resulted in IL-6 production, which was not observed in similarly cultured CD8+ T cells, indicating a role for T cells.

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PubMed1993

Endogenous gamma interferon mediates resistance to Brucella abortus infection.

Depletion of endogenous gamma interferon (IFN-gamma) with anti-IFN-gamma monoclonal antibody resulted in increased numbers of Brucella abortus in the spleen and liver of infected CBA mice. This increase was accompanied by a decrease in splenomegaly and a lower proportion of macrophages in the spleen. Furthermore, treatment of recipient mice with anti-IFN-gamma antibody blocked the adoptive transfer of resistance with immune T cells. Together, the results indicated that endogenous IFN-gamma plays an important role in mediating resistance to primary and secondary Brucella infection.

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PubMed1993

The cellular source of interleukin-6 during Listeria infection.

The cellular source of interleukin-6 (IL-6) during infection of mice with Listeria monocytogenes was investigated both in vitro and in vivo. Peritoneal cells taken at intervals from infected mice and cultured in vitro without added stimulus produced high titers of IL-6 peaking 2 days postinfection in a time course similar to that observed in vivo. Adherent cells with the morphology of macrophages were a major source of this IL-6. Spleen cells similarly harvested at intervals and cultured with heat-killed Listeria or heat-killed Brucella organisms as specific and nonspecific stimuli, respectively, showed two distinct IL-6 responses: (i) an early-phase response up to 5 days after infection when IL-6 production was elicited by either a specific or nonspecific stimulus, and when depletion of T cells had no effect, and (ii) a later response 7 to 10 days after infection when very high levels of IL-6 were produced in response to a specific stimulus. This response was lost when T cells were depleted in vitro or in vivo or in spleen cell cultures from mice with severe combined immunodeficiency. However, studies in vivo failed to show an important role for T cells governing serum IL-6. We conclude that most of IL-6 detected in vivo is produced by nonlymphocytes. Whether IL-6 produced by T lymphocytes in local foci of infection has any role in resolution of that infection is unknown.

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PubMed1993

Cytokine response of T-cell subsets from Brucella abortus-infected mice to soluble Brucella proteins.

Hot saline extracts of Brucella abortus 19 were separated by successive differential precipitation with 50 and 70% ammonium sulfate, yielding fractions SBP50, with predominantly 36-kDa proteins and a number of medium-sized proteins (26 to 33 kDa), and SBP70, with 14-kDa and lower-molecular-mass proteins. Both fractions stimulated specifically proliferation and cytokine production by spleen cells from brucella-infected mice, although the activity of SBP50 was much higher than that of SBP70. Further separation of SBP50 by a DEAE-Sepharose column resulted in three distinct subfractions which were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The three subfractions were analyzed for their abilities to induce lymphocytes to proliferate and produce cytokines. The three subfractions were all active but with characteristic differences in magnitude. Subfraction 1 stimulated moderate proliferation, high interleukin 6 (IL-6) production, and relatively low production of gamma interferon (IFN-gamma). Subfraction 2 was the strongest stimulus for proliferation and production of IL-6 and IFN-gamma, while subfraction 3 stimulated moderate cell proliferation, a high level of IFN-gamma, and a low level of IL-6. IL-2 production stimulated by the three subfractions was similar. SBP50 and all three subfractions stimulated purified T cells of both CD4+ and CD8+ subsets to produce IFN-gamma. The production of IFN-gamma by CD8+ T cells to brucella antigens was enhanced with exogenous IL-2.

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PubMed1993

Cytokine production in the murine response to brucella infection or immunization with antigenic extracts.

In order to induce acquired cellular resistance (ACR) to facultative intracellular bacterial pathogens, infection with live organisms is required. It is possible that different cytokine responses to live bacteria or their extracted antigens could account for their different abilities to induce ACR. Therefore, mice were infected with live attenuated Brucella abortus vaccine strain 19, and their ability to produce cytokines, both in vivo and in vitro, was investigated over 12 weeks of infection. This was compared with the response to injection of soluble brucella proteins (SBP). During infection, serum levels of interleukin-6 (IL-6) were markedly increased over a period of 4 weeks during the peak of infection. SBP plus adjuvant induced a transient increase in serum IL-6. IL-1 and tumour necrosis factor-alpha (TNF-alpha) remained undetectable in both instances. Spleen cells taken at intervals after infection and cultured with brucella antigens produced high titres of IL-6, IL-1 and TNF-alpha. Immunization with SBP was less efficient than live infection at inducing these cytokines. Of the characteristically T-cell-derived lymphokines, interferon-gamma (IFN-gamma) production rose 2 weeks after infection, peaking at 6 weeks, while IL-2 was not detected until 6 weeks post-infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was produced in substantial amounts, but IL-3 production was minimal. In contrast, spleen cells from mice immunized with SBP produced IL-2 but failed to produce IFN-gamma. The implications of these results for the induction of ACR are discussed.

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PubMed1992

Recombinant interleukin-6 protects mice against experimental bacterial infection.

Because of reports of high levels of interleukin-6 (IL-6) in patients during infection, we studied the role of IL-6 in experimental infection. Mice infected with the facultative intracellular pathogen Listeria monocytogenes displayed high levels of IL-6 in their sera and tissues, particularly the spleen, 1 to 3 days after infection. At this time, the IL-6 titers correlated with bacterial numbers in individual mice and in groups of mice given graded doses of Listeria organisms. However, the presence of IL-6 in serum declined after 4 days, even when a large initial dose of bacteria meant that bacterial numbers were still increasing at this time. Recombinant mouse IL-6 injected intraperitoneally before infection protected mice in a dose-dependent manner. It was effective when given 4 h before infection but not when administration was delayed for 24 h postinfection. It is therefore believed that IL-6 plays a role in early priming of the immune response to infection. Its exact function in this model is being investigated.

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PubMed1991

Independently arising macrophage mutants dissociate growth factor-regulated survival and proliferation.

Analysis of a simian virus 40-immortalized colony-stimulating factor 1 (CSF-1) -dependent macrophage cell line (BAC1.2F5) and independently arising autonomous mutants derived from it (aut4A, aut4A.1, aut2A, and aut2A.1) revealed distinct phenotypes. The parental line, BAC1.2F5, is dependent on CSF-1 for survival and growth. Of the mutants derived from BAC1.2F5, aut4A has lost the requirement of CSF-1 for survival; aut4A.1 (derived from aut4A) and aut2A grow in the absence of growth factor but proliferate more rapidly in its presence, and aut2A.1 (derived from aut2A) produces CSF-1 and proliferates as rapidly in the presence as in the absence of exogeneous CSF-1. The separation of the CSF-1 requirement for survival and proliferation observed in aut4A is also observed in a temperature-sensitive (ts) mutant tsgro1. At the nonpermissive temperature, tsgro1 cell proliferation is arrested, but the cells survive provided CSF-1 is present. The four cellular phenotypes observed--immortalization, loss of growth factor requirement for survival, loss of growth factor requirement for proliferation, and loss of growth factor-stimulated proliferation--indicate a divergence of the pathways of growth factor-regulated survival and proliferation and may represent phenotypes occurring at intermediate stages in tumor-cell progression.

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PubMed1991

Prophylaxis or treatment of experimental brucellosis with interleukin-1.

Intravenously injected recombinant human interleukin-1 alpha (IL-1 alpha) given to mice 4 h before infection with Brucella abortus 19 depressed the growth of bacteria in the spleen and liver. However, the same dose (10(5) U) or a 10-fold higher dose was not able to decrease numbers of bacteria when given to chronically infected mice. IL-1 injected into normal mice induced a dramatic increase 2 h later in colony-stimulating activity in serum, measured by bone marrow proliferation, and in colony-stimulating factor 1, measured by radioimmunoassay. Colony-stimulating factor levels declined but remained higher than normal for at least 12 h. The early peak stimulation was not observed in chronically infected mice, but the more prolonged elevation was. As a result of IL-1 treatment, the number of colony-forming cells, especially in the spleen, was increased in normal and acutely or chronically infected mice. Myeloperoxidase staining of newly formed monocytes and polymorphonuclear cells in the spleen revealed an increase in the number of these cells in normal and acutely infected mice as a result of IL-1 treatment, but there was no increase in the already high numbers in chronically infected mice. The relationship between these observations and the basis of chronic infection are discussed.

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PubMed1990

Distinction between 'inflammatory' and 'immune' macrophages killing Listeria monocytogenes in murine infection.

Two populations of efficiently phagocytic and bacteriolytic cells have been defined in the peritoneal cavity following infection of mice with Listeria monocytogenes. One was the result of a transient inflammatory response 2 days after intraperitoneal (i.p.) infection. It consisted of a mixture of monocyte/macrophages and neurotrophils which, when separated on Percoll gradients or by adherence, were both highly bacteriolytic compared with normal resident peritoneal macrophages. It was rich in recently divided cells as evidenced by in vivo labelling with tritiated thymidine. Although having the enlarged, vacuolated appearance of 'activated' macrophages, three-quarters of the monocyte/macrophages stained positive for myeloperoxidase (MPO), characteristic of monocytes rather than mature macrophages. In contrast, intravenous (i.v.) infection, which localizes in spleen and liver, did not produce this early response in the peritoneal cavity. However, 8 days after either i.v. or i.p. infection there existed in the peritoneal cavity a highly active population of cells comprising chiefly macrophages of typical foamy appearance which did not stain for MPO+. They were actively phagocytic and bacteriolytic and, like the early inflammatory exudate, produced increased amounts of oxygen degradative products. They appear to typify the concept of macrophages activated by T cell mediated immunity. Two day peritoneal exudates induced in these previously infected mice by i.p. rechallenge with L. monocytogenes organisms comprised mostly MPO- macrophages.

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PubMed1990

Relationship between colony-stimulating activity and interferon production during infection.

Normal mouse spleen, when cultured in vitro for 3 days in the presence of 10(8) heat-killed Listeria monocytogenes organisms, produced colony-stimulating factors (CSF) that were capable of supporting the production of haemopoietic colonies by bone marrow cells in semi-solid agar, or supporting bone marrow proliferation in liquid medium. In contrast, when the spleen cells were prepared from mice that had been infected with Listeria monocytogenes, colony-stimulating activity (CSA) was no longer detectable over a period from Day 3 to Day 17 post-infection. Suppression of CSA was imposed on normal spleen cells when nylon-wool filtered, T-cell enriched spleen cells from infected mice were co-cultured with normal spleen cells. Suppression largely coincided with the production of interferon by whole spleen from infected mice, and when interferon-gamma (IFN-gamma) was neutralized by antibody CSA was again detected. An early IFN-gamma-independent decrease in CSA production was also detected 2-3 days post-infection. The relevance of this system to the control of CSF production in vivo is discussed.

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