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A M Cooper

Publications and source records attributed to A M Cooper.

At least 37 records · Page 2Linked to original sources
PubMed1998

Adequate expression of protective immunity in the absence of granuloma formation in Mycobacterium tuberculosis-infected mice with a disruption in the intracellular adhesion molecule 1 gene.

It remains unknown whether the expression of cell-mediated protective immunity and the capacity to mount a delayed-type hypersensitivity (DTH) reaction in tuberculosis infection represent two manifestations of a basic response or are dissociable events. In this study, we present data in favor of the latter hypothesis, by showing that tuberculosis infection in the lungs of mice possessing only a truncated form of intracellular adhesion molecule 1 due to gene disruption was still adequately controlled by the expression of protective immunity in the absence of any sustained influx of macrophages and the lack of formation of appreciable granulomas. These animals also had no detectable DTH response to mycobacterial proteins in the footpad assay, indicating that the accumulation of blood-borne macrophages at sites of mycobacterial infection or antigen deposition is not essential to control of the infection. These data support the hypothesis that the DTH component of the cellular response is not protective but contributes by walling off the sites of infection to prevent dissemination and reactivation disease.

Animals↗
PubMed1998

Disruption of the cellular inflammatory response to Listeria monocytogenes infection in mice with disruptions in targeted genes.

The results of this study to dissect the nature of the acquired immune response to infection with Listeria monocytogenes in mice with targetted gene disruptions show that successful resolution of disease requires the essential presence of alphabeta T cells and the capacity to elaborate gamma interferon. In the absence of either of these entities, mice experience increasingly severe hepatitis and tissue necrosis and die within a few days. The data from this study support the hypothesis that the protective process is the efficient replacement of neutrophils in lesions by longer-lived mononuclear phagocytes; alphabeta-T-cell-knockout mice died from progressive infection before neutrophil replacement could occur, whereas in gammadelta-T-cell-knockout mice this replacement process in the liver has previously been shown to be much slower. In the present study we attribute this delay to reduced production of the macrophage-attracting chemokine MCP-1 in the gammadelta-T-cell-knockout animals. These data further support the hypothesis that gammadelta T cells are important in controlling the inflammatory process rather than being essential to the expression of protection.

Animals↗
PubMed1997

Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis.

Immunity to Mycobacterium tuberculosis infection is associated with the emergence of protective CD4 T cells that secrete cytokines, resulting in activation of macrophages and the recruitment of monocytes to initiate granuloma formation. The cytokine-mediating macrophage activation is interferon-gamma (IFN-gamma), which is largely dependent on interleukin-12 (IL-12) for its induction. To address the role of IL-12 in immunity to tuberculosis, IL-12 p40(-/-) mice were infected with M. tuberculosis and their capacity to control bacterial growth and other characteristics of their immune response were determined. The IL-12 p40(-/-) mice were unable to control bacterial growth and this appeared to be linked to the absence of both innate and acquired sources of IFN-gamma. T cell activation as measured by delayed type hypersensitivity and lymphocyte accumulation at the site of infection were both markedly reduced in the IL-12 p40(-/-) mice. Therefore, IL-12 is essential to the generation of a protective immune response to M. tuberculosis, with its main functions being the induction of the expression of IFN-gamma and the activation of antigen-specific lymphocytes capable of creating a protective granuloma.

Animals↗
PubMed1997

An anti-inflammatory role for gamma delta T lymphocytes in acquired immunity to Mycobacterium tuberculosis.

Although a role for gammadelta receptor-bearing T cells in the acquired immune response to infection with Mycobacterium tuberculosis is suggested by several lines of evidence, the only data indicating a possible role in specific protective immunity have been provided by very high dose i.v. infection models. In the current study, more modest low dose inocula delivered by the aerosol route grew identically in wild-type controls and in mutant mice in which the Cdelta gene of the gammadelta TCR has been disrupted by homologous recombination. This situation did not change if the inoculum size was increased or if an aerosol challenge with an M. tuberculosis strain of higher virulence was given. However, while the control and containment of these infections was similar, the mutant mice exhibited a substantial pyogenic form of the granulomatous response compared with the lymphocytic response seen in control animals, a finding that may well explain mortality in the former group if high i.v. doses are given. These data indicate that gammadelta T cells do not directly contribute to protection against tuberculosis or that they do so only when bacterial loads are very high. Instead, the data suggest that gammadelta T cells perhaps play an important role by influencing local cellular traffic, promoting the influx of lymphocytes and monocytes, and limiting the access of inflammatory cells that do not contribute to protection but may cause tissue damage.

Animals↗
PubMed1997

Mycobacterium tuberculosis aerogenic rechallenge infections in B cell-deficient mice.

OBJECTIVE: Use gene disrupted mice to examine the possible role of secretory antibody on resistance to re-exposure to pulmonary tuberculosis. DESIGN: Mice deficient in B cells due to targeted gene disruption were infected by aerosol exposure with Mycobacterium tuberculosis. A further set were identically exposed then given isoniazid to clear the infection and establish a state of memory immunity. RESULTS: Control of the aerosol infection and generation of gamma interferon proceeded in a similar manner in both naive and memory immune mice, regardless of B cell deficiency. CONCLUSIONS: The absence of antibody responses did not affect the course of infection, thus confirming the classical literature that antibody plays no significant protective role.

Aerosols↗
PubMed1997

Expression of memory immunity in the lung following re-exposure to Mycobacterium tuberculosis.

OBJECTIVE: To examine the memory immunity expressed in the lung in response to a low-dose aerosol challenge. DESIGN: Memory-immune C57BL/6 mice were generated by infection followed by drug treatment with isoniazid and rifabutin. Both memory-immune and naive mice were then rechallenged via both the aerosol and intravenous routes. The growth of bacteria in target organs, the expression of cytokines within these organs and the ability of T cells to recognize selected mycobacterial protein antigens were determined over time. RESULTS: There was a finite delay before immunity was expressed in the lungs of the memory-immune mice. This was in contrast to the immediate control of bacterial growth seen in the liver of intravenously challenged mice. In both cases, the expression of interferon-gamma (IFN-gamma) mRNA in the target organ correlated with the control of bacterial growth. Memory immunity in the spleen and lung differed: whereas splenic T cells strongly recognized the major Ag85 protein, the 45 kDa protein, and a synthetic peptide representing the ESAT molecule, only the Ag85 molecule was recognized by T cells harvested from thoracic lymph nodes after pulmonary rechallenge. CONCLUSIONS: Immunity, as mediated by IFN-gamma, is expressed more slowly following an aerosol rechallenge and appears to be restricted in terms of antigen specificity. Moreover, very strong levels of memory immunity can prevent progressive disease in the lungs, but cannot prevent the establishment of secondary infection.

Animals↗
PubMed1997

Evidence for a reduced chemokine response in the lungs of beige mice infected with Mycobacterium avium.

The basis of the increased susceptibility of beige mice to Mycobacterium avium infections is still not clearly understood. In this study we examined the growth of three virulent strains of M. avium in beige mice and normal C57BL/6 controls. Depletion of natural killer (NK) cells by administration of anti-asialo GM1 antisera did not affect the growth of M. avium in any of the groups of animals. Similarly, interferon-gamma (IFN-gamma) gene-disrupted mice were more susceptible to infection than control mice but the growth of M. avium was not further affected by NK-cell depletion. In terms of effector immunity, beige mice showed enhanced expression of IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) when compared with wild-type C57BL/6 mice. In agreement with these results; I-A and interferon-inducible protein (IP-10) expression was also higher in beige mice than in wild-type animals, as was expression of the chemokines macrophage inflammatory protein-2 (MIP-2) and macrophage chemotactic protein (MCP-1) during latter stages of the infection. However, over the first few weeks of the infection, when the susceptibility of the beige mouse lung first becomes evident, MIP-1 beta and MIP-2 chemokine expression in the lungs was lower in beige mice than in wild-type animals. These data indicate, therefore, that the increased susceptibility of beige mice to M. avium infection in the lung is not due to lack of NK-cell activity, nor can it be explained in terms of the effector cytokine response. Instead, the lower early expression of the neutrophil chemoattractants MIP-1 beta and MIP-2 in the lungs of beige mice tends to suggest that the enhanced susceptibility of these mice to M. avium infection may be due in part to defective recruitment of neutrophils or other cells responsive to these specific chemokines.

Animals↗
PubMed1997

The course of Mycobacterium tuberculosis infection in the lungs of mice lacking expression of either perforin- or granzyme-mediated cytolytic mechanisms.

CD8 T cells have been shown to be protective against Mycobacterium tuberculosis infections in the mouse. These cells have been shown to be cytolytic toward M. tuberculosis-infected cells and have also been shown to release the protective cytokine gamma interferon in response to mycobacterial antigen. It has therefore been unclear how these cells mediate their protective response. To dissect this problem, we compared the courses of M. tuberculosis infections in control, perforin gene-knockout, and granzyme gene-knockout mice exposed by the realistic pulmonary route. The inability to express either of these molecules limits the expression of the major lytic pathway but does not appear to influence the course of the infection or result in any discernible histologic differences. These data seem to rule against a lytic role for CD8 T cells in the lungs and hence tend to suggest instead that another type of mechanism, such as cytokine secretion by these cells, is their primary mode of action.

Animals↗
PubMed1996

Antimycobacterial action of thiolactomycin: an inhibitor of fatty acid and mycolic acid synthesis.

Thiolactomycin (TLM) possesses in vivo antimycobacterial activity against the saprophytic strain Mycobacterium smegmatis mc2155 and the virulent strain M. tuberculosis Erdman, resulting in complete inhibition of growth on solid media at 75 and 25 micrograms/ml, respectively. Use of an in vitro murine macrophage model also demonstrated the killing of viable intracellular M. tuberculosis in a dose-dependent manner. Through the use of in vivo [1,2-14C]acetate labeling of M. smegmatis, TLM was shown to inhibit the synthesis of both fatty acids and mycolic acids. However, synthesis of the shorter-chain alpha'-mycolates of M. smegmatis was not inhibited by TLM, whereas synthesis of the characteristic longer-chain alpha-mycolates and epoxymycolates was almost completely inhibited at 75 micrograms/ml. The use of M. smegmatis cell extracts demonstrated that TLM specifically inhibited the mycobacterial acyl carrier protein-dependent type II fatty acid synthase (FAS-II) but not the multifunctional type I fatty acid synthase (FAS-I). In addition, selective inhibition of long-chain mycolate synthesis by TLM was demonstrated in a dose-response manner in purified, cell wall-containing extracts of M. smegmatis cells. The in vivo and in vitro data and knowledge of the mechanism of TLM resistance in Escherichia coli suggest that two distinct TLM targets exist in mycobacteria, the beta-ketoacyl-acyl carrier protein synthases involved in FAS-II and the elongation steps leading to the synthesis of the alpha-mycolates and oxygenated mycolates. The efficacy of TLM against M. smegmatis and M. tuberculosis provides the prospects of identifying fatty acid and mycolic acid biosynthetic genes and revealing a novel range of chemotherapeutic agents directed against M. tuberculosis.

Anti-Bacterial Agents↗
PubMed1995

The protective immune response to Mycobacterium tuberculosis.

Recent advances have characterized the protective immune response against Mycobacterium tuberculosis. These include identification of the phenotype of some protective cells, the antigens to which these cells respond and the cytokines produced in response to infection which modulate disease. Progress has also been made in inducing this response by vaccination.

Animals↗
PubMed1995

The effect of liposomally conjugated methotrexate upon mediator release from human peripheral blood monocytes.

The ability of methotrexate (MTX) and a liposomal preparation containing a lipophilic conjugate of methotrexate (MTX-LIPO) to modulate pro-inflammatory mediator release from lipopolysaccharide-stimulated human peripheral blood monocytes was investigated. At non-toxic concentrations MTX-LIPO (10 micrograms MTX per 250 micrograms lipid) was a potent inhibitor of both IL-1 beta and TNF release resulting in 70.07 +/- 2.3% and 59.19 +/- 2.36% (mean +/- S.E.M.) inhibition, respectively, whereas empty liposomes (E-LIPO; 250 micrograms lipid/well) of the same lipid composition and free MTX (up to 100 micrograms/well) had no effect on either mediator.

Cell Survival↗
PubMed1995

An empirical study of defense mechanisms in panic disorder.

Psychodynamic factors have rarely been systematically studied in panic disorder, despite indications that these factors may be important in the understanding and treatment of panic. This is a report of a study using the Defense Mechanism Rating Scale to test the hypothesis that patients with panic disorder utilize particular defense mechanisms: reaction formation, undoing, and displacement. The use of defense mechanisms in 22 patients with primary panic disorder was compared with that of 22 patients with primary dysthymic disorder, based on Defense Mechanism Rating Scale ratings of psychodynamic interviews of these patients. Panic subjects scored significantly higher than dysthymics on the defenses of reaction formation and undoing, but not on the defense of displacement. The defense mechanisms found are consistent with a proposed psychodynamic formulation for panic disorder that emphasizes the panic patient's difficulty in tolerating angry feelings toward significant others. Knowledge of these defense mechanisms can be useful for various treatment approaches in panic disorder.

Adult↗
PubMed1995

Chemokine response in mice infected with Mycobacterium tuberculosis.

We show here that infection of murine macrophages with various strains of Mycobacterium tuberculosis induces the rapid in vitro expression of genes encoding chemokines macrophage inflammatory protein 1 alpha and macrophage inflammatory protein 2, which recruit neutrophils to sites of infection, and macrophage-recruiting chemokines 10-kDa, interferon-inducible protein (IP-10) and macrophage chemotactic protein 1. Three strains of M. tuberculosis, Erdman and the clinical isolates CSU 22 and CSU 46, induced similar levels of secretion of macrophage chemotactic protein 1 from infected macrophage monolayers; however, the Erdman strain failed to induce levels of secretion of tumor necrosis factor alpha similar to those induced by either CSU 22 or CSU 46. Using a low-dose aerosol infection model, we also found that while the Erdman strain induced negligible increases in chemokine mRNA levels in the lungs, infection with either CSU 22 or CSU 46 resulted in greater levels of mRNA production for all four chemokines tested. The growth of these strains in the lungs was, however, equally well contained by acquired host immunity. These data allow us to hypothesize that the chemokine response in the lungs probably does not control the protective granulomatous response and that perhaps other T-cell- or macrophage-associated cytokines such as tumor necrosis factor alpha or interleukin 12 may be involved in this process.

Animals↗
PubMed1995

Old mice are able to control low-dose aerogenic infections with Mycobacterium tuberculosis.

Previous work in this laboratory has led to the development of the hypothesis that the increased susceptibility of old mice to tuberculosis infection reflects a limited ability by immune CD4 mediator cells to accumulate at sites of bacterial implantation. To test this hypothesis with very low dose infections, the present study documented the course of a low-dose aerogenic infection with virulent Mycobacterium tuberculosis Erdman against time in the target organs of young (3-month-old) and old (24-month-old) B6D2F1 hybrid mice. The results of the study indicated that the infection was controlled by the two groups of mice at similar rates, although the bacterial load in the old mice was eventually somewhat higher. Despite these similarities, some subtle differences between the young and old mice were also evident and included evidence of increased hematogenous spread of the infection from the lungs to other organs in the old mice. Interestingly, very poor expression of the cytokine interleukin-12 was observed in the lungs of infected old mice, leading to the hypothesis that the poor CD4 response in such animals could be partially attributed to the lack of this Th1-type, CD4 T-cell-enhancing cytokine. In this regard, treatment of old mice with exogenous interleukin-12 increased resistance and promoted gamma interferon secretion by CD4 T cells from these mice, although the effects were generally modest. These data suggest that old mice possess CD4-independent compensatory mechanisms by which to deal with low-dose pulmonary tuberculosis infections, although such mechanisms are less efficient than those seen in young animals.

Aerobiosis↗
PubMed1995

The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection.

The early phase of acquired cellular immunity to Mycobacterium tuberculosis infection is mediated by the emergence of protective CD4 T lymphocytes that secrete cytokines including interferon-gamma (IFN-gamma), a molecule which is pivotal in the expression of resistance to tuberculosis. Recent evidence demonstrates that infection with M. tuberculosis induces peripheral blood mononuclear cells to release the cytokine interleukin-12 (IL-12), a molecule that promotes the emergence of T-helper type-1 (Th1), IFN-gamma-producing T cells. We demonstrate here that IL-12 mRNA expression was induced by M. tuberculosis infection both in vivo and in vitro and that exogenous administration of IL-12 to mice transiently resulted in increased resistance to the infection. IL-12 also increased the production of IFN-gamma by both splenocytes derived from infected animals treated in vivo and by antigen-stimulated CD4 cells from untreated infected animals, with maximal effects at times associated with the expansion of antigen-specific CD4 T cells in vivo. In the absence of a T-cell response, as seen in SCID mice or nude mice, IL-12 only slightly augmented the moderate bacteriostatic capacity of these immunocompromised mice. Neutralization of IL-12 by specific monoclonal antibodies resulted in a reduction in granuloma integrity and slowing of the capacity of the animal to control bacterial growth.

Animals↗
PubMed1994

Chronic arterial occlusion associated with Behçet's disease.

We describe two patients with Behçet's disease who developed mild symptoms of chronic upper limb arterial insufficiency. Angiography revealed multiple arterial occlusions. Slowly progressive arterial involvement may occur in Behçet's disease in the absence of significant symptoms.

Adult↗