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Biomedical subjects

A M Cooper

Publications and source records attributed to A M Cooper.

At least 19 recordsLinked to original sources
PubMed2000

Neutrophils play a protective nonphagocytic role in systemic Mycobacterium tuberculosis infection of mice.

Evidence showing that neutrophils play a protective role in the host response to infection by different intracellular parasites has been published in the past few years. We assessed this issue with regard to the infection of mice with Mycobacterium tuberculosis. We found a chronic recruitment of neutrophils to the infection foci, namely, to the peritoneal cavity after intraperitoneal infection and to the spleen and liver after intravenous inoculation of the mycobacteria. However, bacilli were never found associated with the recruited neutrophils but rather were found inside macrophages. The intravenous administration of the antineutrophil monoclonal antibody RB6-8C5 during the first week of infection led to selective and severe neutropenia associated with an enhancement of bacillary growth in the target organs of the mice infected by the intravenous route. The neutropenia-associated exacerbation of infection was most important in the liver, where a bacterial load 10-fold higher than that in nonneutropenic mice was found; the exacerbation in the liver occurred both during and after the neutropenic period. Early in infection by M. tuberculosis, neutropenic mice expressed lower levels of mRNAs for gamma interferon and inducible nitric oxide synthase in the liver compared to nondepleted mice. These results point to a protective role of neutrophils in the host defense mechanisms against M. tuberculosis, which occurs early in the infection and is not associated with the phagocytic activity of neutrophils but may be of an immunomodulatory nature.

Animals↗
PubMed2000

Transient loss of resistance to pulmonary tuberculosis in p47(phox-/-) mice.

Mycobacterium tuberculosis is an important respiratory pathogen the growth of which is controlled primarily by cytokine-activated macrophages. One of the principal mediators of this control is nitric oxide; however, superoxide has recently been shown to be protective in systemic mycobacterial infections. To determine whether superoxide is important in controlling M. tuberculosis during primary pulmonary infection, mice lacking the cytosolic p47(phox) gene (which is essential for effective superoxide production by the NADPH oxidase) were infected aerogenically. The lack of superoxide during an aerosol infection with M. tuberculosis resulted in a significant increase in bacterial growth over the early period of infection. Once antigen-specific gamma interferon-producing lymphocytes were detected in the draining lymph nodes, however, bacterial growth in the lung stopped. One interesting consequence of the lack of superoxide was an increase in neutrophilic infiltrates within the granuloma. This may be a consequence of increased tissue damage due to more rapid bacterial growth or may reflect a role for superoxide in controlling inflammation.

Animals↗
PubMed2000

Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection.

Immunity to Mycobacterium tuberculosis is dependent upon the generation of a protective gamma interferon (IFN-gamma)-producing T-cell response. Recent studies have suggested that interleukin-6 (IL-6) is required for the induction of a protective T-cell response and that IL-4 may suppress the induction of IFN-gamma. To evaluate the role of the cytokines IL-6 and IL-4 in the generation of pulmonary immunity to M. tuberculosis, IL-6 and IL-4 knockout mice were infected with M. tuberculosis via aerosol. The absence of IL-6 led to an early increase in bacterial load with a concurrent delay in the induction of IFN-gamma. However, mice were able to contain and control bacterial growth and developed a protective memory response to secondary infection. This demonstrates that while IL-6 is involved in stimulating early IFN-gamma production, it is not essential for the development of protective immunity against M. tuberculosis. In contrast, while the absence of IL-4 resulted in increased IFN-gamma production, this had no significant effect upon bacterial growth.

Animals↗
PubMed1999

Total body and regional bone mineral density in men: effect of age.

Bone density is related to the risk of fracture, with a decrease in bone density resulting in an increased risk of fracture. The aims of this study were to characterize the relationship between bone mineral density (BMD) and age at different skeletal sites in men, and to determine whether the BMD pattern with age reflects the pattern of fracture in men. We studied 178 healthy Caucasian men, ages 20-79 years (approximately 30 per decade) from a general practitioner register. Spinal radiographs were obtained from men over 50 years of age and graded by a radiologist for spinal osteoarthritis by the method of Kellgren. BMD was measured by dual-energy X-ray absorptiometry at the anteroposterior (AP) lumbar spine, femoral neck, Ward's triangle, trochanter, ultradistal forearm and total body (providing estimates for the pelvis, head, arms, legs, trunk, ribs and spine). Severe osteoarthritis (grades 3 and 4) was associated with increased spine BMD, and therefore individuals with severe osteoarthritis were excluded from analysis of the spine. There was a decrease in height of vertebrae L2-4 in men between 20 and 79 years of age (4%), resulting in a decrease in projected area. The change in BMD in standard deviation units (T-score) between 20 and 79 years was calculated: there were significant decreases at the femoral neck (-1.6), Ward's triangle (-2.4), total body (-0.6), and its subregions the pelvis (-1.4), trunk (-0.8), ribs (-0.7) and legs (-0.7). There was no change in BMD with age at the AP lumbar spine, ultradistal forearm, or the total body subregion of the head. Similar results were found after adjusting for height and weight. Thus, there was only a small decrease in total body BMD across life, but a substantial decrease in BMD of the pelvis and proximal femur, sites rich in trabecular bone. These are the same sites associated with substantial increases in fracture incidence in men with aging.

Adult↗
PubMed1999

Cytokine/chemokine cascades in immunity to tuberculosis.

The relationship between acquired specific resistance and delayed-type hypersensitivity (DTH) in immunity to tuberculosis has long been a topic of debate. Here, Ian Orme and Andrea Cooper propose that the events are separate mechanisms; protection is cytokine driven and initially controls the infection, whereas DTH is primarily chemokine driven and functions to wall off the infection and prevent further dissemination.

Animals↗
PubMed1999

Antimycobacterial activities of isoxyl and new derivatives through the inhibition of mycolic acid synthesis.

Isoxyl (ISO), a thiourea (thiocarlide; 4, 4'-diisoamyloxythiocarbanilide), demonstrated potent activity against Mycobacterium tuberculosis H37Rv (MIC, 2.5 micrograms/ml), Mycobacterium bovis BCG (MIC, 0.5 microgram/ml), Mycobacterium avium (MIC, 2.0 microgram/ml), and Mycobacterium aurum A+ (MIC, 2.0 microgram/ml), resulting in complete inhibition of mycobacteria grown on solid media. Importantly, a panel of clinical isolates of M. tuberculosis from different geographical areas with various drug resistance patterns were all sensitive to ISO in the range of 1 to 10 microgram/ml. In a murine macrophage model, ISO exhibited bactericidal killing of viable intracellular M. tuberculosis in a dose-dependent manner (0.05 to 2.50 microgram/ml). The selective action of ISO on mycolic acid synthesis was studied through the use of [1, 2-14C]acetate labeling of M. tuberculosis H37Rv, M. bovis BCG, and M. aurum A+. At its MIC for M. tuberculosis, ISO inhibited the synthesis of both fatty acids and mycolic acids (alpha-mycolates by 91.6%, methoxymycolates by 94.3%, and ketomycolates by 91.1%); at its MIC in M. bovis BCG, ISO inhibited the synthesis of alpha-mycolates by 87.2% and that of ketomycolates by 88.5%; and the corresponding inhibitions for M. aurum A+ were 87.1% for alpha-mycolates, 87.2% for ketomycolates, and 86.5% for the wax-ester mycolates. A comparison with isoniazid (INH) and ethionamide (ETH) demonstrated marked similarity in action, i.e., inhibition of the synthesis of all kinds of mycolic acids. However, unlike INH and ETH, ISO also inhibited the synthesis of shorter-chain fatty acids. ISO showed no acute toxicity against primary macrophage cell cultures as demonstrated by diminution of redox activity. A homologous series of ISO derivatives were synthesized. Most derivatives were as effective or more effective than the parent compound in the agar proportion assay. Thus, these thioureas, like INH and ETH, specifically inhibit mycolic acid synthesis and show promise in counteracting a wide variety of drug-sensitive and -resistant strains of M. tuberculosis.

Antitubercular Agents↗
PubMed1999

Resistance of virulent Mycobacterium avium to gamma interferon-mediated antimicrobial activity suggests additional signals for induction of mycobacteriostasis.

The cytokine gamma interferon (IFN-gamma) plays a major role in the control of Mycobacterium avium infections. We assessed whether the progressive growth of virulent strains of M. avium was associated with alterations in the production of this cytokine as evaluated by reverse transcription-PCR and detection of immunoreactive cytokine in the serum and in spleen homogenates. We found that IFN-gamma was induced during infection by a virulent strain of M. avium to similar or even higher extents than the levels found during infections by a less virulent strain whose growth was controlled. IFN-gamma produced during infection by both mycobacterial strains was partly derived from T cells and led to activation of macrophages, namely, those that were infected. Concomitant with the development of the infection with the virulent strain of M. avium there was an extensive depletion of lymphocytes in the spleen. Thymectomy alone promoted the proliferation of the virulent, but not of the less virulent, strain of M. avium. Our data indicate that virulent strains of M. avium resist the antimicrobial mechanisms of IFN-gamma-activated macrophages and raise the possibility that a second, T-cell-dependent signal is required for the effective control of mycobacterial replication inside macrophages.

Animals↗
PubMed1998

Immunopathogenesis of Mycobacterium avium infection.

One of the most obvious problems one perceives when working with Mycobacterium avium isolates is the vast array of phenotypes expressed with regard to colonial morphotype, serovar and particularly virulence. Thus whenever experimental data derived from different MAC isolates is compared the variety of this group of mycobacteria must always be considered. Another issue of concern is the extrapolation of in vitro data to the in vivo disease. We have reported, in the past, that survival in murine macrophage culture does not always correlate with survival in vivo (23). It is plausible therefore, that the pathways outlined in section 5.2 and figure 3 play a crucial role in the initiation of the innate immune response in general and that there are components of this response which are not expressed by IFN-gamma activated macrophages but which are necessary for bacterial control. In conclusion, we suggest that the initial control of MAC infection requires a healthy lung (or gut) architecture and that control by unactivated macrophages includes respiratory burst activity and also the sequestration of free iron away from the mycobacterial phagosome. Acquired immunity is important in controlling bacteria which have overcome the innate response and this control is mediated by cytokine activation of infected macrophages. Finally, we have described an animal model of infection in which uncontrolled bacterial growth occurs and in which lesions similar to those seen in AIDS patients develop.

Animals↗
PubMed1998

Role of gamma delta T cells in immunopathology of pulmonary Mycobacterium avium infection in mice.

Several studies have shown that gamma delta T cells influence granuloma development after infection with intracellular pathogens. The role of gamma delta T cells in controlling the influx of inflammatory cells into the lung after Mycobacterium avium infection was therefore examined with gene-disrupted mice (K/O). The mice were infected with either M. avium 724, a progressively replicating highly virulent strain of M. avium, or with M. avium 2-151 SmT, a virulent strain that induces a chronic infection. gamma delta-K/O mice infected with M. avium 2-151 SmT showed early enhanced bacterial growth within the lung compared to the wild-type mice, although granuloma formation was similar in both strains. gamma delta-K/O mice infected with M. avium 724 showed identical bacterial growth within the lung compared to the wild-type mice, but they developed more-compact lymphocytic granulomas and did not show the extensive neutrophil influx and widespread tissue necrosis seen in wild-type mice. These data support the hypothesis that isolates of M. avium that induce protective T-cell-specific immunity are largely unaffected by the absence of gammadelta T cells. Whereas with bacterial strains that induce poor protective immunity, the absence of gamma delta T cells led to significant reductions in both the influx of neutrophils and tissue damage within the lungs of infected mice.

Animals↗
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↗