Douglas B Lowrie - Profile on Academia.edu (original) (raw)
Papers by Douglas B Lowrie
Use of 3- O -methyI- D -glucose and phloretin to estimate the intracellular water space of mouse peritoneal macrophage monolayers
Canadian Journal of Physiology and Pharmacology, 1982
Despite over 30 years of intermittent investigations, there is no definitive evidence that macrop... more Despite over 30 years of intermittent investigations, there is no definitive evidence that macrophages kill Mycobacterium tuberculosis. This is largely because all attempts to demonstrate such killing by macrophages in vitro have produced only rather unconvincing results. How then can I discuss how macrophages kill tubercle bacilli when it is not proven that they do? The answer is that just as there is a large and growing body of indirect evidence that makes it highly likely that macrophages can kill tubercle bacilli, there is also a body of evidence that makes it likely that they do so by producing hydrogen peroxide.
Vaccine Against Mycobacterial Infections
British Medical Bulletin, 1988
Hydrogen peroxide-dependent and lysosomal mechanisms can operate against mycobacteria in macropha... more Hydrogen peroxide-dependent and lysosomal mechanisms can operate against mycobacteria in macrophages. The relative importance of these mechanisms against the different mycobacteria is still unclear with recent studies lending little further support to earlier evidence for peroxide-mediated killing Impairment of lysosome function, through inhibition of fusion or escape into the cytoplasm, is an established phenomenon but we still can only guess at its significance. Intracellular bacteriostasis is a frequent manifestation of immunological activation of macrophages but the mechanisms and significance of this too are unclear.
Issues facing TB control (8). The future of BCG/vaccine development
Scottish medical journal, 2000
Journal of General Microbiology, 1978
At sub-bactericidal concentrations of hydrogen peroxide, Mycobacterium tuberculosis was killed by... more At sub-bactericidal concentrations of hydrogen peroxide, Mycobacterium tuberculosis was killed by hydrogen peroxide/peroxidase/halide microbicidal systems. The halide cofactor could be either iodide or, with much lower efficiency, chloride. Omission of any one of the reactants eliminated the tuberculocidal effect. Differences in susceptibility between different strains of M . tuberculosis did not correlate with virulence differences. The observations are discussed in the context of host defence mechanisms against tuberculosis. Downloaded from www.microbiologyresearch.org by IP: 54.92.132.4 On: Sun, 10 Jul 2016 01:29:55 274 P. S. JACKETT, V. R. ABER A N D D. B. L O W R I E
Journal of general microbiology, 1979
When ingested by mouse peritoneal macrophage monolayers, live Mycobacterium microti caused a sust... more When ingested by mouse peritoneal macrophage monolayers, live Mycobacterium microti caused a sustained increase in monolayer cyclic AMP content and fusion of lysosomes with the bacterium-containing phagosomes was impaired. Ingested live M. bovis BCG caused a transient increase in cyclic AMP and the defect in phagolysosome formation was less pronounced. Dead mycobacteria and live M. lepraemurium neither enhanced monolayer cyclic AMP content nor inhibited phagolysosome formation. Mycobacterium microti and BCG exceeded M. lepraemurium in cyclic AMP-synthesizing activity in vitro but the question of whether bacterial cyclic AMP contributed substantially to the increments in infected macrophages was not resolved. Antibody-coated BCG retained the ability to synthesize cyclic AMP and to enhance monolayer cyclic AMP but lost the ability to inhibit phagolysosome formation in macrophages, The observations are discussed in terms of possible control of phagolysosome formation by cyclic nucleoti...
The Biochemical journal, Jan 15, 1979
Macrophages were obtained by pulmonary lavage from normal rabbits or rabbits that had developed p... more Macrophages were obtained by pulmonary lavage from normal rabbits or rabbits that had developed pulmonary granulomas after receiving intravenous BCG vaccine 2-3 weeks earlier. The cells were disrupted in iso-osmotic sucrose and a low-speed supernatant was fractionated by isopycnic centrifugation on a linear sucrose density gradient. Three populations of hydrolase-containing granules (putative lysosomes) were found in both normal and BCG-induced macrophages. They were distinguished by their different distributions in the gradient and different sensitivities to disruption by digitonin and were termed:type A, containing lysozyme; type B, containing N-acetyl-beta-glucosaminidase, beta-glactosidase, beta-glucuronidase and possibly some lysozyme; type C, containing cathepsin D. Acid phosphatase appeared to be about equally distributed between type B and C granules. Type A and B granules from BCG-induced macrophages showed markedly greater equilibrium density than did those from normal mac...
Biochimica et biophysica acta, Jan 11, 1980
Normal and Bacillus Calmette-Guerin (BCG) vaccine-induced rabbit alveolar macrophage homogenates ... more Normal and Bacillus Calmette-Guerin (BCG) vaccine-induced rabbit alveolar macrophage homogenates were fractionated by isopycnic density gradient centrifugation. Superoxide dismutase-inhibitable NAD(P)H-dependent nitro-blue tetrazolium reductase was found localised to endoplasmic reticulum and mitochondria. The normal macrophages tended to contain more of this activity than the BCG-induced macrophages. Two superoxide dismutases were found: cyanide-sensitive superoxide dismutase was predominantly present in the cytosol, with a small proportion in mitochondria; cyanide-resistant superoxide dismutase was found confined to mitochondria. Neither differed in specific activity betw-en the normal and BCG-induced macrophages.
Guinea pig alveolar macrophages probably kill M. tuberculosis H37Rv and H37Ra in vivo by producing hydrogen peroxide
Advances in experimental medicine and biology, 1983
DNA Vaccination: An Update
Vaccine Protocols, 2003
1. Methods Mol Med. 2003;87:377-90. DNA vaccination: an update. Lowrie DB. National Institute for... more 1. Methods Mol Med. 2003;87:377-90. DNA vaccination: an update. Lowrie DB. National Institute for Medical Research, The Ridgeway, London, United Kingdom. PMID: 12958468 [PubMed - indexed for MEDLINE]. Publication Types: Review. MeSH Terms: ...
Vaccine, 2006
DNA vaccines that were being investigated in mice for prophylactic use against tuberculosis were ... more DNA vaccines that were being investigated in mice for prophylactic use against tuberculosis were soon found also to be surprisingly effective as treatment against established infection. The immune system was stimulated to kill the bacteria, even including the persistent latent bacteria that are otherwise refractory to the immune system and antibacterial chemotherapeutic drugs alike. Subsequent results from a range of laboratories using diverse DNA vaccines in diverse murine models of infection have been very varied, ranging from enhanced pathology, through negligible effects, to major additive benefit from combined vaccine and chemotherapy. This review summarises the data and assesses future prospects.
The Journal of Infectious Diseases, 2007
The increasing threat posed by drug-resistant strains of M. tuberculosis is leading to a reapprai... more The increasing threat posed by drug-resistant strains of M. tuberculosis is leading to a reappraisal of the possibility of treating tuberculosis (TB) by immunotherapy. We analyze 6 strategies that have been shown to be therapeutic in animal models of TB and identify a common pathway underlying the activity of the superficially different immunotherapeutic protocols. This pathway involves enhanced induction of CD8 + cytotoxic T lymphocytes (CTLs) and down-regulation of interleukin-4 and transforming growth factor-b, leading to further enhancement of the activity of CD8 + CTLs and of other microbicidal pathways. This unifying analysis strengthens the rationale for future trials of immunotherapy in humans and points to surrogate markers that could be studied in such trials. 65-kDa hsp65 DNA vaccine. R.H.-P. has recently received funding from SR Pharma to cover the costs of exploring the effects of oral M. vaccae in the mouse model of pulmonary tuberculosis, although the published work described in the review was not subject to any payments, and he has received funding from Hollis-Eden to cover the costs of testing the steroid HE2000 in the BALB/ c mouse model.
Editorial [Hot Topic: Tuberculosis (Part 1) (Guest Editor: Douglas B. Lowrie)]
Current Molecular Medicine, 2007
ABSTRACT It is some twenty years since the first genes were cloned from pathogenic mycobacteria a... more ABSTRACT It is some twenty years since the first genes were cloned from pathogenic mycobacteria and 8 years since the complete DNA sequence of a Mycobacterium tuberculosis genome was published. When the first genes were cloned TB was commonly regarded as a beaten disease; we had fully effective chemotherapy, an adequate vaccine (BCG) and the remaining problem (people dying elsewhere) was to be solved by field operational and socio-economic developments. The declaration by the World Health Organization in 1993 that tuberculosis had become “A Global Emergency” certainly helped to change the perception that TB was a beaten disease and, although the emphasis remained on the operational issues of improving the application of the existing control measures, particularly DOTS chemotherapy, there was a surge in basic research. This is fortunate, since there has been little sign that the global emergency (2 million deaths a year) is coming under control by application of the existing tools. On the contrary, extremely drug resistant (XDR) TB is disseminating, bringing with it the 40-60% death rates that prevailed in the pre-chemotherapy era. Equally, there is no sign that the synergy between HIV and TB that is devastating some parts of the world, and spreading, is being brought under control either. There is typically a long lag between basic research and applied benefits and the length of that lag is inversely proportional to the financial resources mobilized. The resources have been paltry in relation to the scale of the problem and the benefits to be gained. Yet, already we have attained a dramatically increased understanding of the bacterium and how it goes about its business of growing, causing disease and spreading. Conceptual changes have been brought about and new drugs and new vaccines have been devised. Many of these are reviewed in this issue of the journal. The first four reviews deal with basic studies of the mycobacterium, which may underpin and inform efforts directly aimed at developing new practical tools for disease control. Cox and Cook have drawn together remarkable new insights into the metabolic pathways and growth regulation of the tubercle bacillus and derived mathematical relationships between key variables. Dover et al. provide a comprehensive review of the detailed level at which the synthesis of the complex cell wall is now understood and Bacon and Marsh review the unexpected ways in which the bacteria respond to controlled changes in single environmental variables. Waddell and Butcher discuss the evidence and implications of the findings that the metabolism of the bacterium inside infected cells is dramatically different from its metabolism in conventional laboratory conditions. Whereas the basic studies can be viewed as providing the basis for rational design of new tools, particularly bactericidal drugs aimed at key aspects of bacterial persistence and growth in vivo, the extent to which this is currently being achieved can be assessed in the review of new drug discovery by Williams and Duncan. On the other hand, the molecular typing of strains of tubercle bacillus has developed directly and rapidly out of basic studies and has filled a glaring gap in the TB control toolbox, as reviewed by Behr and Mostowy. The immunology of tuberculosis is proving slow to yield its secrets and undergo paradigm shifts. Accordingly, there is a lack or immune correlates of protection that can be applied to people to predict either the outcome of infection or the effect of vaccination and this unsatisfactory situation is surveyed by Fletcher; clinical evaluation of new vaccines could be severely delayed if adequate correlates are not found soon.Support for a hypothesis relating excessive type 2 (Th2) immune responses to failure of immunity through inadequate bactericidal and cytotoxic T cell responses is drawn together by Rook. In relation to vaccine composition, insight into the role and potential utility of bacterial heat shock proteins as antigens and adjuvants in immunity is reviewed by Walker et al. The thrust for new fully defined and synthetic vaccines to complement or replace the live BCG vaccine is epitomised by the work reviewed by McMurry et al. and efforts to refine and enhance BCG itself by genetic engineering are reviewed by Hernandez-Pando et al. Although the potential of immunotherapy as an adjunct to chemotherapy has been largely ignored until now, encouraging indications of what might be achievable have been obtained in mice and the current position is summarised by Roy et al..........
Biochemical Pharmacology, 1982
4C]Benzylpenicillin was rapidly taken up into and eluted from mouse peritoneal macrophage monolay... more 4C]Benzylpenicillin was rapidly taken up into and eluted from mouse peritoneal macrophage monolayers and entered cytosol, lysosomes and phagolysosomes containing Staphylococcus aureus. Equilibrium concentrations in cytosol and lysosomes were consistent with transport by diffusion but partial membrane carrier dependence was evidenced by saturability (K, and V,,,,, 110 mM and 117 nmoles * Present address:
Use of 3- O -methyI- D -glucose and phloretin to estimate the intracellular water space of mouse peritoneal macrophage monolayers
Canadian Journal of Physiology and Pharmacology, 1982
Despite over 30 years of intermittent investigations, there is no definitive evidence that macrop... more Despite over 30 years of intermittent investigations, there is no definitive evidence that macrophages kill Mycobacterium tuberculosis. This is largely because all attempts to demonstrate such killing by macrophages in vitro have produced only rather unconvincing results. How then can I discuss how macrophages kill tubercle bacilli when it is not proven that they do? The answer is that just as there is a large and growing body of indirect evidence that makes it highly likely that macrophages can kill tubercle bacilli, there is also a body of evidence that makes it likely that they do so by producing hydrogen peroxide.
Vaccine Against Mycobacterial Infections
British Medical Bulletin, 1988
Hydrogen peroxide-dependent and lysosomal mechanisms can operate against mycobacteria in macropha... more Hydrogen peroxide-dependent and lysosomal mechanisms can operate against mycobacteria in macrophages. The relative importance of these mechanisms against the different mycobacteria is still unclear with recent studies lending little further support to earlier evidence for peroxide-mediated killing Impairment of lysosome function, through inhibition of fusion or escape into the cytoplasm, is an established phenomenon but we still can only guess at its significance. Intracellular bacteriostasis is a frequent manifestation of immunological activation of macrophages but the mechanisms and significance of this too are unclear.
Issues facing TB control (8). The future of BCG/vaccine development
Scottish medical journal, 2000
Journal of General Microbiology, 1978
At sub-bactericidal concentrations of hydrogen peroxide, Mycobacterium tuberculosis was killed by... more At sub-bactericidal concentrations of hydrogen peroxide, Mycobacterium tuberculosis was killed by hydrogen peroxide/peroxidase/halide microbicidal systems. The halide cofactor could be either iodide or, with much lower efficiency, chloride. Omission of any one of the reactants eliminated the tuberculocidal effect. Differences in susceptibility between different strains of M . tuberculosis did not correlate with virulence differences. The observations are discussed in the context of host defence mechanisms against tuberculosis. Downloaded from www.microbiologyresearch.org by IP: 54.92.132.4 On: Sun, 10 Jul 2016 01:29:55 274 P. S. JACKETT, V. R. ABER A N D D. B. L O W R I E
Journal of general microbiology, 1979
When ingested by mouse peritoneal macrophage monolayers, live Mycobacterium microti caused a sust... more When ingested by mouse peritoneal macrophage monolayers, live Mycobacterium microti caused a sustained increase in monolayer cyclic AMP content and fusion of lysosomes with the bacterium-containing phagosomes was impaired. Ingested live M. bovis BCG caused a transient increase in cyclic AMP and the defect in phagolysosome formation was less pronounced. Dead mycobacteria and live M. lepraemurium neither enhanced monolayer cyclic AMP content nor inhibited phagolysosome formation. Mycobacterium microti and BCG exceeded M. lepraemurium in cyclic AMP-synthesizing activity in vitro but the question of whether bacterial cyclic AMP contributed substantially to the increments in infected macrophages was not resolved. Antibody-coated BCG retained the ability to synthesize cyclic AMP and to enhance monolayer cyclic AMP but lost the ability to inhibit phagolysosome formation in macrophages, The observations are discussed in terms of possible control of phagolysosome formation by cyclic nucleoti...
The Biochemical journal, Jan 15, 1979
Macrophages were obtained by pulmonary lavage from normal rabbits or rabbits that had developed p... more Macrophages were obtained by pulmonary lavage from normal rabbits or rabbits that had developed pulmonary granulomas after receiving intravenous BCG vaccine 2-3 weeks earlier. The cells were disrupted in iso-osmotic sucrose and a low-speed supernatant was fractionated by isopycnic centrifugation on a linear sucrose density gradient. Three populations of hydrolase-containing granules (putative lysosomes) were found in both normal and BCG-induced macrophages. They were distinguished by their different distributions in the gradient and different sensitivities to disruption by digitonin and were termed:type A, containing lysozyme; type B, containing N-acetyl-beta-glucosaminidase, beta-glactosidase, beta-glucuronidase and possibly some lysozyme; type C, containing cathepsin D. Acid phosphatase appeared to be about equally distributed between type B and C granules. Type A and B granules from BCG-induced macrophages showed markedly greater equilibrium density than did those from normal mac...
Biochimica et biophysica acta, Jan 11, 1980
Normal and Bacillus Calmette-Guerin (BCG) vaccine-induced rabbit alveolar macrophage homogenates ... more Normal and Bacillus Calmette-Guerin (BCG) vaccine-induced rabbit alveolar macrophage homogenates were fractionated by isopycnic density gradient centrifugation. Superoxide dismutase-inhibitable NAD(P)H-dependent nitro-blue tetrazolium reductase was found localised to endoplasmic reticulum and mitochondria. The normal macrophages tended to contain more of this activity than the BCG-induced macrophages. Two superoxide dismutases were found: cyanide-sensitive superoxide dismutase was predominantly present in the cytosol, with a small proportion in mitochondria; cyanide-resistant superoxide dismutase was found confined to mitochondria. Neither differed in specific activity betw-en the normal and BCG-induced macrophages.
Guinea pig alveolar macrophages probably kill M. tuberculosis H37Rv and H37Ra in vivo by producing hydrogen peroxide
Advances in experimental medicine and biology, 1983
DNA Vaccination: An Update
Vaccine Protocols, 2003
1. Methods Mol Med. 2003;87:377-90. DNA vaccination: an update. Lowrie DB. National Institute for... more 1. Methods Mol Med. 2003;87:377-90. DNA vaccination: an update. Lowrie DB. National Institute for Medical Research, The Ridgeway, London, United Kingdom. PMID: 12958468 [PubMed - indexed for MEDLINE]. Publication Types: Review. MeSH Terms: ...
Vaccine, 2006
DNA vaccines that were being investigated in mice for prophylactic use against tuberculosis were ... more DNA vaccines that were being investigated in mice for prophylactic use against tuberculosis were soon found also to be surprisingly effective as treatment against established infection. The immune system was stimulated to kill the bacteria, even including the persistent latent bacteria that are otherwise refractory to the immune system and antibacterial chemotherapeutic drugs alike. Subsequent results from a range of laboratories using diverse DNA vaccines in diverse murine models of infection have been very varied, ranging from enhanced pathology, through negligible effects, to major additive benefit from combined vaccine and chemotherapy. This review summarises the data and assesses future prospects.
The Journal of Infectious Diseases, 2007
The increasing threat posed by drug-resistant strains of M. tuberculosis is leading to a reapprai... more The increasing threat posed by drug-resistant strains of M. tuberculosis is leading to a reappraisal of the possibility of treating tuberculosis (TB) by immunotherapy. We analyze 6 strategies that have been shown to be therapeutic in animal models of TB and identify a common pathway underlying the activity of the superficially different immunotherapeutic protocols. This pathway involves enhanced induction of CD8 + cytotoxic T lymphocytes (CTLs) and down-regulation of interleukin-4 and transforming growth factor-b, leading to further enhancement of the activity of CD8 + CTLs and of other microbicidal pathways. This unifying analysis strengthens the rationale for future trials of immunotherapy in humans and points to surrogate markers that could be studied in such trials. 65-kDa hsp65 DNA vaccine. R.H.-P. has recently received funding from SR Pharma to cover the costs of exploring the effects of oral M. vaccae in the mouse model of pulmonary tuberculosis, although the published work described in the review was not subject to any payments, and he has received funding from Hollis-Eden to cover the costs of testing the steroid HE2000 in the BALB/ c mouse model.
Editorial [Hot Topic: Tuberculosis (Part 1) (Guest Editor: Douglas B. Lowrie)]
Current Molecular Medicine, 2007
ABSTRACT It is some twenty years since the first genes were cloned from pathogenic mycobacteria a... more ABSTRACT It is some twenty years since the first genes were cloned from pathogenic mycobacteria and 8 years since the complete DNA sequence of a Mycobacterium tuberculosis genome was published. When the first genes were cloned TB was commonly regarded as a beaten disease; we had fully effective chemotherapy, an adequate vaccine (BCG) and the remaining problem (people dying elsewhere) was to be solved by field operational and socio-economic developments. The declaration by the World Health Organization in 1993 that tuberculosis had become “A Global Emergency” certainly helped to change the perception that TB was a beaten disease and, although the emphasis remained on the operational issues of improving the application of the existing control measures, particularly DOTS chemotherapy, there was a surge in basic research. This is fortunate, since there has been little sign that the global emergency (2 million deaths a year) is coming under control by application of the existing tools. On the contrary, extremely drug resistant (XDR) TB is disseminating, bringing with it the 40-60% death rates that prevailed in the pre-chemotherapy era. Equally, there is no sign that the synergy between HIV and TB that is devastating some parts of the world, and spreading, is being brought under control either. There is typically a long lag between basic research and applied benefits and the length of that lag is inversely proportional to the financial resources mobilized. The resources have been paltry in relation to the scale of the problem and the benefits to be gained. Yet, already we have attained a dramatically increased understanding of the bacterium and how it goes about its business of growing, causing disease and spreading. Conceptual changes have been brought about and new drugs and new vaccines have been devised. Many of these are reviewed in this issue of the journal. The first four reviews deal with basic studies of the mycobacterium, which may underpin and inform efforts directly aimed at developing new practical tools for disease control. Cox and Cook have drawn together remarkable new insights into the metabolic pathways and growth regulation of the tubercle bacillus and derived mathematical relationships between key variables. Dover et al. provide a comprehensive review of the detailed level at which the synthesis of the complex cell wall is now understood and Bacon and Marsh review the unexpected ways in which the bacteria respond to controlled changes in single environmental variables. Waddell and Butcher discuss the evidence and implications of the findings that the metabolism of the bacterium inside infected cells is dramatically different from its metabolism in conventional laboratory conditions. Whereas the basic studies can be viewed as providing the basis for rational design of new tools, particularly bactericidal drugs aimed at key aspects of bacterial persistence and growth in vivo, the extent to which this is currently being achieved can be assessed in the review of new drug discovery by Williams and Duncan. On the other hand, the molecular typing of strains of tubercle bacillus has developed directly and rapidly out of basic studies and has filled a glaring gap in the TB control toolbox, as reviewed by Behr and Mostowy. The immunology of tuberculosis is proving slow to yield its secrets and undergo paradigm shifts. Accordingly, there is a lack or immune correlates of protection that can be applied to people to predict either the outcome of infection or the effect of vaccination and this unsatisfactory situation is surveyed by Fletcher; clinical evaluation of new vaccines could be severely delayed if adequate correlates are not found soon.Support for a hypothesis relating excessive type 2 (Th2) immune responses to failure of immunity through inadequate bactericidal and cytotoxic T cell responses is drawn together by Rook. In relation to vaccine composition, insight into the role and potential utility of bacterial heat shock proteins as antigens and adjuvants in immunity is reviewed by Walker et al. The thrust for new fully defined and synthetic vaccines to complement or replace the live BCG vaccine is epitomised by the work reviewed by McMurry et al. and efforts to refine and enhance BCG itself by genetic engineering are reviewed by Hernandez-Pando et al. Although the potential of immunotherapy as an adjunct to chemotherapy has been largely ignored until now, encouraging indications of what might be achievable have been obtained in mice and the current position is summarised by Roy et al..........
Biochemical Pharmacology, 1982
4C]Benzylpenicillin was rapidly taken up into and eluted from mouse peritoneal macrophage monolay... more 4C]Benzylpenicillin was rapidly taken up into and eluted from mouse peritoneal macrophage monolayers and entered cytosol, lysosomes and phagolysosomes containing Staphylococcus aureus. Equilibrium concentrations in cytosol and lysosomes were consistent with transport by diffusion but partial membrane carrier dependence was evidenced by saturability (K, and V,,,,, 110 mM and 117 nmoles * Present address: