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C G Mackintosh

Publications and source records attributed to C G Mackintosh.

At least 19 recordsLinked to original sources
PubMed2001

Optimal models to evaluate the protective efficacy of tuberculosis vaccines.

BCG has been used widely as a vaccine to prevent tuberculosis (TB) for 80 years, yet there is still considerable controversy about its efficacy. Many experimental variables have obscured the true efficacy of BCG. The absence of appropriate animal models for the study of protective efficacy and the lack of in vitro correlates of protective immunity have impeded progress. Laboratory animal studies, which have contributed to understanding the pathogenesis, heritability of resistance and immunology of TB, have failed to identify the immunological pathways necessary for protective immunity. In recent years, cattle and deer, which are naturally susceptible to TB, have been used to study protective immunity in vaccinated animals, challenged with virulent bacteria. A deer TB infection model has been developed that can measure protection against TB infection or the development of disease. Data from this model show that, providing live BCG is administered in a short interval prime-boost protocol, significant protection against infection and disease can be obtained. Single dose vaccine provides suboptimal protection that attenuates pathology but does not prevent infection. Low dose BCG vaccine (10(4)cfu), administered in a prime-boost protocol, sufficient to prevent infection, does not cause conversion to delayed type hypersensitivity or produce unacceptable side-effects. Immune memory for protection against infection persists at optimal levels for at least 12 months post vaccination. Used optimally, BCG produces good levels of protection against TB and improved protocols or its use should be explored, before attempts are made to replace it with new-generation vaccines. It is now possible to integrate the fundamental information obtained from laboratory animals with studies of functional immune protection in target host species. Justification for the use of TB vaccines for domestic livestock under field conditions, must be underpinned by scientific evidence that they provide acceptable levels of protection long term.

Animals↗
PubMed2001

Mycobacterium bovis in free-living and captive wildlife, including farmed deer.

Mycobacterium bovis has been isolated from a wide range of wildlife species, in addition to domestic animals. This review examines the role played by various species in the maintenance of M. bovis in wildlife communities and the spread to domestic animals. Badgers (Meles meles), brushtail possums (Trichosurus vulpecula), deer (Odocoileus virginianus), bison (Bison bison) and African buffalo (Syncerus caffer) are examples of wildlife that are maintenance hosts of M. bovis. The importance of these hosts has been highlighted by the growing realisation that these animals can represent the principal source of infection for both domestic animals and protected wildlife species. The range of methods for controlling M. bovis in wildlife is limited. While population control has been used in some countries, this approach is not applicable in many situations where protected wildlife species are concerned. Vaccination is a potential alternative control method, although as yet, no practical, effective system has been developed for vaccinating wildlife against bovine tuberculosis. Tuberculosis caused by M. bovis has also been a problem in captive wildlife and in recently domesticated animals such as farmed deer. Control of M. bovis in this group of animals is dependent on the judicious use of diagnostic tests and the application of sound disease control principles. The advances in the development of bovine tuberculosis vaccines for cattle and farmed deer may offer valuable insights into the use of vaccination for the control of tuberculosis in a range of captive wildlife species.

Africa↗
PubMed2000

Oral infection of ferrets with virulent Mycobacterium bovis or Mycobacterium avium: susceptibility, pathogenesis and immune response.

Ferrets are important wildlife reservoirs of tuberculosis in New Zealand, where they acquire infection primarily through scavenging infected carrion. In the present study, groups of laboratory-reared ferrets were infected orally with 5 x 10(6)colony-forming units of Mycobacterium bovis or Mycobacterium avium. Body weight and tuberculin-specific immune reactivity were monitored at intervals (pre-infection, and 4 and 20 weeks post-infection) and animals were killed at 20 weeks post-infection for post-mortem, histopathological and bacteriological examinations. Weight loss was significantly greater in M. bovis -infected than in M. avium -infected ferrets. M. bovis, unlike M. avium, sometimes produced gross necrotic lesions in the mesenteric lymph nodes. M. bovis invariably produced microscopical foci of mycobacterial infection or tissue necrosis typical of tuberculosis, whereas M. avium did so in only one of nine animals. Mycobacteria were recovered from the lymphatic tissues of all M. bovis -infected ferrets but from only five of nine M. avium -infected animals; and the mean bacterial burdens of the lymph nodes of the head and intestinal regions were > 10-fold and > 100-fold greater, respectively, for M. bovis -infected than for M. avium -infected animals. M. bovis, unlike M. avium, evoked tuberculin-specific peripheral blood lymphocyte reactivity and serum antibody responses.

Animals↗
PubMed2000

Tuberculosis in deer: perceptions, problems and progress.

Since the emergence of deer farming as an alternative farming enterprise over the past 30 years, there has been an increasing awareness of the potential threat posed by tuberculosis (TB) to domesticated deer. TB, caused by Mycobacterium bovis, has been found in deer in every country involved with deer farming. Different types of TB control policies, which vary from whole-herd depopulation to selective testing and slaughter of reactor animals, have been implemented. Extensive research has been carried out, incorporating modern microbiological and immunological concepts and advanced molecular methodologies, to find new solutions for the eradication of TB from domesticated deer. This work has resulted in valuable new insights into the aetiology, transmission, pathogenesis, diagnosis, prevention and heritability of resistance to M. bovis infection in ruminants. This knowledge has complemented the existing literature database on bovine and human TB and will provide new strategies for improved diagnosis, vaccination and selective breeding to control TB, which should be relevant for human, domestic livestock and wildlife populations.

Animals↗
PubMed2000

Mycobacterium bovis-infected cervine alveolar macrophages secrete lymphoreactive lipid antigens.

Tuberculosis is caused by intracellular bacteria belonging to the genus Mycobacterium, including M. tuberculosis and M. bovis. Alveolar macrophages (AMs) are the primary host cell for inhaled mycobacteria. However, little is known about the mechanisms by which infected AMs can process and present mycobacterial antigens to primed lymphocytes and how these responses may affect ensuing protection in the host. In the present study, we sought to determine whether AMs from a naturally susceptible host for Mycobacterium bovis (red deer) could produce and secrete soluble immunoreactive antigens following mycobacterial infection in vitro. Confluent monolayers of deer AMs were infected with either heat-killed or live virulent M. bovis or M. bovis BCG at a multiplicity of infection of 5:1 and cultured for 48 h. Culture supernatants were collected, concentrated, and tested for the presence of mycobacterial antigens in a lymphocyte proliferation assay by using peripheral blood mononuclear cells from M. bovis-sensitized or naive deer. Supernatants derived from macrophages which had been infected with live bacilli stimulated the proliferation of antigen-sensitized, but not naive, lymphocytes. Supernatants derived from uninoculated AMs or AMs inoculated with heat-killed bacilli failed to stimulate lymphocyte proliferation. The lymphoproliferative activity was retained following lipid extraction of the supernatants, which were free of amino groups as determined by thin-layer chromatography. These results demonstrate that mycobacteria which are actively growing within AMs produce lipids which are secreted into the extracellular milieu and that these lipids are recognized by lymphocytes from mycobacterium-primed hosts. We suggest that mycobacterial lipids are released from AMs following aerosol infection in vivo and that they play an important role in the early immune response to tuberculosis.

Animals↗
PubMed2000

Genetic resistance to experimental infection with Mycobacterium bovis in red deer (Cervus elaphus).

Tuberculosis (Tb) caused by Mycobacterium bovis is a worldwide threat to livestock and humans. One control strategy is to breed livestock that are more resistant to Mycobacterium bovis. In a 3-year heritability study 6 farmed red deer stags were selected from 39 on the basis of their differing responses to experimental challenge via the tonsillar sac with approximately 500 CFU of M. bovis. Two stags remained uninfected, two were moderately affected, and two developed serious spreading Tb. Seventy offspring, bred from these six stags by artificial insemination using stored semen, were similarly challenged with M. bovis. The offspring showed patterns of response to M. bovis challenge similar to those of their sires, providing evidence for a strong genetic basis to resistance to Tb, with an estimated heritability of 0.48 (standard error, 0.096; P < 0. 01). This is the first time the heritability of Tb resistance in domestic livestock has been measured. The breeding of selection lines of resistant and susceptible deer will provide an ideal model to study the mechanisms of Tb resistance in a ruminant and could provide an additional strategy for reducing the number and severity of outbreaks of Tb in farmed deer herds. Laboratory studies to identify genetic and immunological markers for resistance to Tb are under way. Preliminary studies showed no associations between NRAMP or DRB genes and resistance to Tb in deer. Patterns of immune responses seen in resistant animals suggest that both innate and acquired pathways of immunity are necessary to produce the resistant phenotype.

Animals↗
PubMed2000

Systemic but not intra-intestinal vaccination with BCG reduces the severity of tuberculosis infection in ferrets (Mustela furo).

SETTING: Ferrets are important wildlife vectors of bovine tuberculosis (Mycobacterium bovis) in New Zealand. By reducing the severity and/or incidence of tuberculosis (TB) in wild ferret populations, vaccination may limit disease transmission to livestock. OBJECTIVE: To investigate whether vaccination of ferrets with attenuated M. bovis BCG via systemic or intraintestinal routes can reduce the severity of TB resulting from oral M. bovis challenge. DESIGN: Groups of captive ferrets were vaccinated with live BCG via sub-cutaneous injection or intra-duodenal inoculation, twice, 4 weeks apart. Vaccinated and non-vaccinated (control) ferrets were subsequently challenged orally with virulent M. bovis to simulate the natural route of infection. Peripheral blood lymphocyte reactivity was longitudinally monitored, and the outcome of challenge was determined 20 weeks later by autopsy, histology and bacteriological culture. RESULT: Both vaccination routes induced tuberculin-specific lymphocyte reactivity; however, only the subcutaneous route was effective in reducing disease. Subcutaneous vaccinated ferrets had a lower severity of infection than non-vaccinated control animals, as indicated by significant reductions in viable bacterial burdens and prevention of gross lesions in mesenteric lymph nodes (the primary site of infection), and a lower incidence of bacterial translocation to thoracic lymph nodes. However, sub-cutaneous vaccination did not reduce the incidence of mesenteric lymph node infection. CONCLUSIONS: Systemic vaccination with BCG can reduce the severity of TB resulting from oral challenge with virulent M. bovis; however, delivery of viable BCG to the upper intestinal tract may not protect ferrets against TB.

Animals↗
PubMed1999

Intracellular survival of virulent Mycobacterium bovis and M. bovis BCG in ferret macrophages.

The intracellular survival of virulent Mycobacterium bovis and avirulent M. bovis BCG in ferret alveolar macrophages was investigated. In addition, the effects of endogenous and exogenous modulators of macrophage oxidative function on bacterial survival and growth in vitro were determined. Ferret macrophages limited the initial growth of BCG, while virulent M. bovis replicated within macrophages. Intracellular bacterial survival was unaffected by the addition of specific inhibitors of macrophage oxidative function. A T-cell supernatant (TCS), derived from mitogen-stimulated lymphocyte cultures, activated ferret macrophages for heightened oxidative burst performance. However, macrophages activated by TCS, bacterial LPS or a combination of both, failed to control infection, and actually enhanced the intracellular survival of M. bovis. These results are discussed in relation to the role of macrophages in mediating tuberculosis-related pathogenesis, with respect to the fact that ferrets are important wildlife vectors of bovine tuberculosis in New Zealand.

Animals↗
PubMed1999

Oxidative responses in ferret macrophages.

Although the basic function of T and B lymphocytes in ferrets has been known for some time, the function of mononuclear phagocytes has not been described in this species. The present study has characterised basic oxidative responses in ferret macrophages, and has investigated the effects of endogenous and exogenous modulators of macrophage function on oxidative capacity in vitro. Macrophages derived from the blood or lungs of ferrets were shown capable of generating the reactive oxygen intermediate (ROI) molecules superoxide and hydrogen peroxide, and secreting a lysosomal enzyme (acid phosphatase), in response to appropriate stimuli. A T cell supernatant (derived from mitogen-stimulated peripheral blood lymphocytes) was able to activate both blood- and lung-derived macrophages for enhanced ROI production, while specific ROI inhibitors (superoxide dismutase and catalase) were able to partially ablate ROI activity. The accumulation of nitrite in culture supernatants, as an indicator for the production of reactive nitrogen intermediates, could not be demonstrated by ferret macrophages derived from either tissue source. In contrast to the enhancing effects of TCS on the oxidative function of blood-derived macrophages, exposure to bacterial LPS caused marked suppression of ROI and lysosomal enzyme production by these cells. Finally, the generation of superoxide anion, following phagocytosis of live or heat-killed Mycobacterium bovis or zymosan, indicated that ROI production in response to phagocytic stimulation was relatively weak in ferret blood-derived macrophages. These results are discussed in relation to the study of immune function in a novel species, and with particular reference to research into tuberculosis (Tb), since ferrets are important wildlife vectors of bovine Tb in New Zealand.

Animals↗
PubMed1999

Vaccine protocols to optimise the protective efficacy of BCG.

SETTING: A deer model has been developed to study protection produced with BCG vaccination, against infection and the development of pathology, following experimental intratonsilar infection with virulent Mycobacterium bovis. OBJECTIVE: To determine how the dose of vaccine, the route of vaccination, the viability of the vaccine and exposure to glucocorticoids at the time of vaccination, may affect the protective efficacy of BCG vaccines. DESIGN: Deer were vaccinated with BCG and later challenged with virulent M. bovis via the tonsilar route. Protection against infection and development of disease was evaluated at necropsy six months after challenge with M. bovis, by histological examination and microbial culture. RESULTS: Significant protection against infection and disease were obtained following boosting with two low doses (5 x 10(4) cfu) or moderate doses (5 x 10(7) cfu) of live (freshly cultured and lyophilized) BCG. Inferior levels of protection were obtained with high dose (5 x 10(8) cfu) of live BCG. Similar levels of protection were found with vaccines given subcutaneously or via the tonsilar route. Killed vaccine in a mineral-oil adjuvant did not evoke protective immunity and treatment with dexamethasone prior to vaccination with live BCG ablated its efficacy. Protection against infection did not correlate with skin test delayed type hypersensitivity (DTH) or lymphocyte transformation to tuberculin. CONCLUSIONS: Two doses of live BCG gave significant protection against experimental infection and disease caused by virulent M. bovis. Single dose vaccine protected against disease but not infection. Vaccines administered at a dosage which did not evoke DTH, provided protection against tuberculosis infection and disease.

Adjuvants, Immunologic↗
PubMed1999

Partial protection against oral challenge with Mycobacterium bovis in ferrets (Mustela furo) following oral vaccination with BCG.

SETTING: Ferrets (Mustela furo) are important wildlife vectors of bovine tuberculosis (TB) in New Zealand. Protective vaccination of ferrets may limit the potential of transmission to livestock. OBJECTIVE: To determine whether orally-delivered Mycobacterium bovis BCG can confer protection against oral challenge with virulent M. bovis. DESIGN: Ten ferrets were vaccinated by feeding measured doses of live BCG, and subsequently challenged with virulent M. bovis via the oral route. Ten non-vaccinated (control) ferrets were similarly challenged. Live body weights and lymphocyte reactivity were monitored longitudinally, and ferrets were killed 20 weeks following challenge. Necropsy, histological examination and bacterial culture of alimentary tract lymphatic tissues were undertaken. RESULTS: There was a significant reduction in the incidence of gross tuberculous lesions among vaccinated ferrets compared to control animals, and fewer vaccinated ferrets had histologically-detectable acid-fast organisms in mesenteric lymph node (LN) tissues. There were significantly fewer vaccinated ferrets with culture-positive retropharyngeal LNs, and the mean bacterial burden was significantly lower for retropharyngeal LNs isolated from vaccinated animals than from controls. CONCLUSION: These results demonstrate that oral BCG vaccination of ferrets can confer partial protection against M. bovis, and suggest that systemic immune responses may be less important in mediating this degree of protection than local immunity.

Animals↗
PubMed1998

Interpreting comparative experiments on parasite burdens in animals using randomization and canonical variates.

Comparative experiments on parasite burdens present difficulties for modelling and interpretation: data tend to have highly skewed distributions, some standard methods of testing for effects have low power, and there is a need to make allowance for dependencies among the various measurements. Randomization testing and canonical variates analysis are advocated as a means of minimising these problems.

Abomasum↗
PubMed1998

Deer health and disease.

This paper describes the most significant diseases of farmed deer which have emerged over the last 30 or so years. It describes their characteristic signs, how control measures have evolved, their current status and gives an indication of future diagnostic and control measures. Overall, it shows that wild deer brought into a farming environment have developed some of the production limiting diseases which affect sheep and cattle, such as parasitism and trace element deficiencies. In addition, farmed deer are susceptible to potentially fatal diseases such as tuberculosis, malignant catarrhal fever and yersiniosis. A disease which has recently emerged and has the potential to be more serious than any of the above is Johne's disease. In North America, Chronic Wasting Disease occurs in captive and wild deer in only two states but has the potential to be a serious threat to wild and farmed deer elsewhere if it spreads. The zoonotic risks of diseases affecting deer are discussed, as well as stress, welfare and deer restraint. The productivity of farmed deer can be maximised by using a well-designed deer health programme integrated with good management and feeding.

Animal Diseases↗
PubMed1995

Animal models of protective immunity in tuberculosis to evaluate candidate vaccines.

While the etiology of tuberculosis is well understood, the nature of the protective immune response to the causative mycobacteria has remained a mystery. There is an urgent need to define protective immunity critically, and to develop alternative animal models to evaluate the efficacy of new-generation vaccines against tuberculosis in a cost-effective way.

Animals↗
PubMed1993

BCG vaccination in deer: distinctions between delayed type hypersensitivity and laboratory parameters of immunity.

Groups of deer were vaccinated with live or killed Bacillus Calmette-Guerin (BCG), with and without oil adjuvant, to compare their immune responses with those found in naturally infected animals. Killed BCG in oil induced strong lymphocyte transformation (LT) and antibody (ELISA) responses specific for Mycobacterium bovis antigens. Serum inflammatory proteins (SIP) were also induced after these animals were skin tested. This pattern of reactivity mirrored that found in naturally infected deer with active tuberculosis. Animals vaccinated with live BCG without oil adjuvant also produced strong LT reactivity but this was directed at common mycobacterial antigens found on both M. bovis and M. avium, although no antibody or SIP were detected at any stage of the experiment. The pattern of immune responsiveness to live BCG was similar to that found in naturally infected, but non-diseased deer, and may represent the immunoprotective response to tuberculosis. Significant differences in specificity of lymphocyte transformation and intradermal skin test reactivity to mycobacterial antigens were also identified. Vaccination with BCG in various formulations provides an experimental probe to evaluate the immunological basis of immunity to tuberculosis.

Animals↗
PubMed1991

Evaluation of relationship between plasma fibrinogen concentration and tuberculin testing in red deer.

After intradermal injection of bovine purified derivative (PPD), increases in plasma fibrinogen concentration and plasma viscosity developed in red deer (Cervus elaphus) with a history of tuberculosis caused by Mycobacterium bovis. Serum haptoglobin concentrations were also found to increase under similar circumstances. The increases were reproducible and did not appear to be related to mustering, stress, or the handling associated with injection of PPD. A significant (P less than 0.05) direct relationship was found between the increase in plasma fibrinogen concentration and various markers of bovine tuberculosis infection, such as stimulation of lymphocyte transformation in response to bovine PPD and the diameter of intradermal tuberculin skin test reactions. A stronger correlation (P less than 0.01) was found with the volume of intradermal tuberculin skin test reactivity, and the strongest correlation (P less than 0.001) was with the presence of circulating antibovine PPD antibody.

Animals↗
PubMed1988

Effect of physical restraint and xylazine sedation on haematological values in red deer (Cervus elaphus).

Blood samples were taken from healthy red deer (Cervus elaphus) using physical restraint or xylazine sedation. Red and white cell and platelet parameters were measured using a Technicon H6000/C analyser. Lower circulating red cell mass, lymphocyte and platelet counts were found in sedated deer. Mean red cell volume was significantly lower, probably due to the preferential sequestration of young red cells in the spleen. While the main cause of the observed differences is likely to be splenic contraction during physical restraint, the lower plasma viscosity and fibrinogen are suggestive of a haemodynamic component.

Animals↗