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Biomedical subjects

G A Rook

Publications and source records attributed to G A Rook.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cortisol metabolism, cortisol sensitivity and the pathogenesis of leprosy reactions.

The concentration of cortisol in a tissue is regulated by a reversible enzyme 'shuttle' that can deactivate cortisol by converting it to cortisone, or activate cortisone by converting it to cortisol. The activity of this shuttle, and the direction in which it operates, is regulated by numerous factors including cytokines. This results in large swings in the effective cortisol concentration in sites of inflammation at different phases of an inflammatory response. Thus changes in local cortisol concentration can be largely independent of circulating cortisol levels. The relevant shuttle enzymes are present in skin, blood vessels and nervous tissue, and inhibition of the enzymes in skin enhances the local anti-inflammatory effect of cortisol. We therefore suggest that changes in the activity or direction of action of the shuttle in leprosy lesions may predispose to reactions, requiring exogenous steroid supplements to regain control of the inflammation.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Glucocorticoids and immune function.

The prevailing notion has been that cytokines such as interleukin-1 released from sites of inflammation cross the blood-brain barrier and drive the hypothalamo-pituitary-adrenal (HPA) axis so that cortisol is released into the circulation to exert indiscriminate systemic anti-inflammatory effects. It is now clear that feedback from the HPA axis is subject to more subtle and localized regulation. The signal that activates cortisol release travels to the hypothalamus via vagal sensory afferents (so the brain 'knows' where the inflammation is), and the effects of the released cortisol are regulated within individual tissues via numerous mechanisms, including changes in the affinity of the cortisol receptors, and changes in the equilibrium point of the cortisol/cortisone shuttle (11 beta hydroxysteroid dehydrogenases 1 and 2). This equilibrium is locally regulated by cytokines. These mechanisms are central to the regulation of the balance of Th1 to Th2 cytokines within sites of inflammation, and to the appropriate or inappropriate termination of the inflammatory response in infections or autoimmunity.

Cortisone↗
PubMed1998

Immunological and endocrinological characteristics of tuberculosis that provide opportunities for immunotherapeutic intervention.

Immunity to tuberculosis requires a T helper 1 (Th1) response which can be compromised by excessive release of inflammatory cytokines or Th2 activity. Environmental saprophytes can protect against tuberculosis by inducing Th1 recognition of the common antigens, or make mice more susceptible to tuberculosis than unimmunized controls by evoking a Th2 response. A mixed Th1 + Th2 response increases the local toxicity of tumour necrosis factor alpha (TNF-alpha). Some saprophytes are potent immunogens. A killed preparation of Mycobacterium vaccae can cause systemic activation of spontaneously Th1 cytokine-secreting cells in humans, and can non-specifically suppress pre-existing IgE formation and interleukin 5 (IL-5) production in murine models of allergy. These effects, and the Th2-inducing effects of other species, may explain the variable efficacy of Bacillus Calmette-Guérin, and suggest the need for new approaches to the screening of vaccines before trial in humans. The balance of Th1 to Th2 and the function of inflammatory cytokines are also regulated by cortisol. Glucocorticoid metabolism is abnormal in tuberculosis, suggesting overactivity of 11-beta-hydroxysteroid reductase enzymes. The reductase activity of these enzymes is enhanced by TNF-alpha and IL-1 beta. The roles of Th2, inflammatory cytokines, common antigens and changes in cortisol metabolism suggest several strategies for immunotherapy, and several sites where genetic polymorphisms may affect susceptibility.

BCG Vaccine↗
PubMed1998

Give us this day our daily germs.

Modern vaccinations, fear of germs and obsession with hygiene are depriving the immune system of the information input upon which it is dependent. This fails to maintain the correct cytokine balance and fine-tune T-cell regulation, and may lead to increased incidences of allergies and autoimmune diseases. If humans continue to deprive their immune systems of the input to which evolution has adapted it, it may be necessary to devise ways of replacing it artificially.

Adult↗
PubMed1998

Inhibition of an established allergic response to ovalbumin in BALB/c mice by killed Mycobacterium vaccae.

Allergic disorders are mediated by T lymphocytes secreting T helper 2 (Th2) cytokines, interleukin-4 (IL-4) and interleukin-5 (IL-5), resulting in high levels of serum immunoglobulin E (IgE) and recruitment of eosinophils. One of the treatment strategies is to downregulate the Th2 component by inducing a T helper 1 (Th1) response to the relevant allergen, because Th1 and Th2 cytokines are thought to be mutually antagonistic. In this study, we examined the effects of Mycobacterium vaccae, a potent inducer of Th1 immunity, on allergic responses in a murine model. A single injection of M. vaccae into ovalbumin (OVA)-preimmunized BALB/c mice suppressed serum IgE over a wide dose range (10(7), 10(8) or 10(9) M. vaccae). Further experiments, using 10(7) M. vaccae injected twice, showed that this treatment inhibited not only serum IgE, but also the potential for ovalbumin-induced IL-5 production by spleen cells. This non-specific ability of a mycobacterium to decrease Th2 activity, even when not presented together with the allergen, is in agreement with recent epidemiological studies on the impact of bacillus Calmette-Guérin (BCG) vaccination, and of other potent Th1 stimuli, on the incidence of atopy. The suppression of serum IgE and allergen-specific IL-5 synthesis by M. vaccae suggest that this organism is likely to have clinical application in the immunotherapy of allergy.

Animals↗
PubMed1998

Changes in cellular response to mycobacterial antigens and cytokine production patterns in leprosy patients during multiple drug therapy.

Changes in Mycobacterium leprae-induced lymphoproliferative responses and mediator release by leprosy patients' lymphocytes were followed during multiple drug therapy (MDT). At the time of diagnosis, multibacillary (MB) patients who did not develop reactions responded to both sonicated M. leprae and synthetic disaccharide coupled to bovine serum albumin (ND-BSA) antigens, but those who would later develop reactions did not respond, even in the presence of added cytokines. The paucibacillary (PB) group initially had high responses to sonicated M. leprae but no response to ND-BSA, even in the presence of added cytokines. In the first year of treatment, the supernatants of PB patients' cell cultures contained factors that enhanced the phytohaemagglutinin (PHA) response of normal cells. In contrast, those MB patients who did not develop reactions at a later stage produced culture supernatants that were inhibitory. Interestingly, the MB patients who later developed reactions during treatment, and did not initially respond to M. leprae, produced supernatants containing enhancing factors, like those of the PB group. Later on in the treatment, all patients had the same patterns: when response to M. leprae decreased from its highest level, inhibitory factors were produced. Further studies revealed that the supernatants which inhibited the PHA response of normal cells contained the active form of transforming growth factor-beta 1, (TGF-beta 1), whatever the disease type or treatment status of the donor. These TGF-beta 1 levels correlated directly with the degree of inhibition. Similarly supernatants that neither inhibited nor enhanced PHA responses contained the highest levels of interleukin-10 (IL-10), while those from treated patients that enhanced contained the lowest levels of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma). These cytokine correlations transcended the conventional disease classification, and imply that all patients pass through a sequence of patterns of immune response during treatment. These treatment-induced changes may explain occasional reports of response patterns at variance with the 'immunological spectrum' of leprosy.

Adolescent↗
PubMed1998

The effects of androstenediol and dehydroepiandrosterone on the course and cytokine profile of tuberculosis in BALB/c mice.

Immunity to Mycobacterium tuberculosis requires a T helper 1 (Th1) cytokine balance accompanied by tumour necrosis factor-alpha (TNF-alpha), and activated macrophages. These facets of the immune response are sensitive to suppression by glucocorticoids (GC), which can reactivate and exacerbate tuberculosis in man and animals. Dehydroepiandrosterone (DHEA) and its derivative, 3beta,17beta androstenediol (AED), are reported to have antiglucocorticoid properties in vivo. We therefore investigated the effects of predetermined optimal doses of these compounds, on the course of pulmonary tuberculosis in an established model in BALB/c mice in which an early phase of Th1-mediated response accompanied by adrenal hyperplasia, is followed by a switch to Th2, progressive loss of TNF-alpha expression and disease progression. Both compounds were protective, particularly AED which caused a fall in bacterial counts and prolonged survival. These effects correlated with the appearance within 3 days of cellular infiltrates rich in cells expressing interleukin-2 (IL-2), IL-1alpha and TNF-alpha, and with partial suppression of the switch to IL-4 producing cells that occurred in controls. AED also caused enhanced development of granulomas at 14 days, and persistence of granuloma formation to 120 days, with a corresponding suppression of areas affected by pneumonia. Much of the therapeutic effect of AED and DHEA was obtained by treating for only the first 3 weeks, which is the phase of adrenal hyperplasia. These results suggest that the ratio of GC to anti-GC steroids may play a role in the pathogenesis of tuberculosis, and further investigation could lead to novel treatment strategies.

Androstenediol↗
PubMed1998

Emergent immunoregulatory properties of combined glucocorticoid and anti-glucocorticoid steroids in a model of tuberculosis.

In Balb/c mice with pulmonary tuberculosis, there is a switch from a protective Th1-dominated cytokine profile to a non-protective profile with a Th2 component. This switch occurs while the adrenals are undergoing marked hyperplasia. Treatment with the anti-glucocorticoid hormones dehydroepiandrosterone or 3 beta, 17 beta-androstenediol, during the period of adrenal hyperplasia, maintains Th1 dominance and is protective. We investigated the effects of these hormones as therapeutic agents by administering them from day 60, when the switch to the non-protective cytokine profile was already well established. Given at this time (day 60), doses that were protective when given early (from day 0) were rapidly fatal. A physiological dose of the glucocorticoid corticosterone was also rapidly fatal. However when the corticosterone and the anti-glucocorticoid (AED or DHEA) were co-administered, there was protection, with restoration of a Th1-dominated cytokine profile, enhanced DTH responses, and enhanced expression of IL-1 alpha and TNF alpha. Therefore this combination of steroids has an emergent property that is quite unlike that of either type of steroid given alone. It may be possible to exploit the ant-inflammatory properties of glucocorticoids while preserving a Th1 bias, by combining glucocorticoids with DHEA or suitable metabolites.

Adjuvants, Immunologic↗
PubMed1998

Pulmonary bovine-type tuberculosis in rabbits: bacillary virulence, inhaled dose effects, tuberculin sensitivity, and Mycobacterium vaccae immunotherapy.

This report elucidates four aspects of the immunology of pulmonary tuberculosis produced in rabbits: (i) the virulence of bovine-type tubercle bacilli, strain Ravenel S, (ii) systemic factors influencing the generation of visible primary pulmonary tubercles, (iii) differences in tuberculin sensitivity of rabbits and humans, and (iv) the effect of Mycobacterium vaccae immunotherapy on cavitary tuberculosis. Laboratory strain Ravenel S (ATCC 35720) was not fully virulent. Fully virulent strains produce one visible primary pulmonary tubercle for each three bacillary units inhaled. Strain ATCC 35720 produced one such tubercle for each 18 to 107 bacillary units inhaled, indicating that its virulence was reduced by 6- to 36-fold. When a low dose of this Ravenel S strain was inhaled, the host resistance (measured by the number of inhaled bacilli needed to generate one visible primary pulmonary tubercle) was increased at least 3.5-fold compared to the host resistance when a high dose was inhaled. Rabbits and humans differ in the degree and in the maintenance of their dermal sensitivities to tuberculin. Compared to rabbits, humans are 100 times more sensitive to tuberculin. Also, at 33 weeks rabbits with well-controlled cavitary tuberculosis usually showed a decrease in their tuberculin reactions of about 50% from peak values, whereas humans with such well-controlled tuberculosis are thought to maintain strong reactions for many years. These species differences may be due to desensitization to group II mycobacterial antigens in the rabbits because they have a different diet and a different type of digestive tract. M. vaccae immunotherapy of rabbits with cavitary tuberculosis produced no statistically significant effects. Experiments with many more rabbits would be required to prove whether or not such immunotherapy is beneficial.

Animals↗
PubMed1997

Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile?

The symptoms of Gulf War syndrome are compatible with the hypothesis that the immune system of affected individuals is biased towards a Th2-cytokine pattern. Factors that could lead to a Th2 shift among Gulf War veterans include exposure to multiple Th2-inducing vaccinations under stressful circumstances and the way in which such vaccinations were administered, which would be expected to maximise Th2 immunogenicity. These factors may have led to a long-term systemic shift towards a Th2-cytokine balance and to mood changes related to the immunoendocrine state. Other vaccines that lead to similar long-term, non-specific shifts in cytokine balance are well-established. If our hypothesis is proven, treatment may be possible with regimens that induce a systemic Th1 bias.

Affect↗
PubMed1997

Pathogenetic role, in human and murine tuberculosis, of changes in the peripheral metabolism of glucocorticoids and antiglucocorticoids.

Immunity to tuberculosis (TB) requires a Th1 pattern of cytokine release, dominated by interleukin-2 (IL-2) and interferon gamma (IFN gamma). In experimental models even a minor Th2 component (characterized by production of IL-4) abrogates immunity, and leads to an immunopathology that mimics the human disease. Increased exposure of T cells to glucocorticoids drives them towards a Th2 cytokine profile and could therefore help to explain the presence of an inappropriate Th2 component in TB. Analysis of adrenal steroid metabolites in 24-h urine collections revealed a striking increase in metabolites of active cortisol relative to metabolites of inactive cortisone. This indicates a change in the balance of 11 beta-hydroxysteroid dehydrogenase to 11 beta-ketosteroid reductase. The site of this disease-associated alteration in reductase/dehydrogenase balance may be the lung. The lung contains 11 beta HSD-1, (a reversible oxido-reductase) which in the liver works as a reductase. In the normal lung it functions paradoxically as a reductase, but it can alter its function in the presence of cytokines. TB patients (like other ill individuals) also show reduced 24-h urinary secretion of dehydroepiandrosterone (DHEA) derivatives. Since these have antiglucocorticoid functions in vivo, this fall may exacerbate the effects of the reduced inactivation of cortisol and loss of diurnal rhythm, and contribute to immunological dysfunction. Recent studies of TB in mice, and in children during infancy, adrenarche and puberty, suggest that the ratio of cortisol to DHEA may be crucial both to susceptibility and to the pathology of the disease that develops.

Animals↗
PubMed1997

Variation within Mycobacterium scrofulaceum.

The purpose of this study was to identify Mycobacterium scrofulaceum reliably and rapidly and investigate diversity within the species. Fifty-four cultures were identified as Myco. scrofulaceum by preliminary cultural and biochemical tests, thin-layer chromatography and double diffusion. These strains were examined by PCR based on the 65 kDa heat stress protein gene, followed by restriction enzyme analysis of the product with BstEII and HaeIII. This produced seven groups, most with fewer fragments than had been reported previously. The technique was a rapid and reliable method for studying variation within Myco. scrofulaceum but alone, was unable to discriminate between some of these variants and other genetically similar species. When PCR-RFLP results were combined with biochemical tests, the major groups appeared to relate to different disease situations and thus, may have some epidemiological value.

DNA, Bacterial↗
PubMed1997

HIV infection alters the production of both type 1 and 2 cytokines but does not induce a polarized type 1 or 2 state.

OBJECTIVE: To test the T-helper (TH)1/TH2 cytokine paradigm in HIV infection. DESIGN AND METHODS: Cytokine profiles in two separate studies of HIV patients and controls are presented: (i) a longitudinal study of HIV patients with CD4 counts > 500 x 10(6)/l tested at three timepoints compared with controls; (ii) a blinded cross-sectional study of controls and patients with high (> 500 x 10(6)/l) and low (< 500 x 10(6)/l) CD4 counts. Peripheral blood mononuclear cells (PBMC) from patients and controls were tested for the production of two type 1 [interleukin (IL)-2, interferon (IFN)-gamma] and two type 2 (IL-4, IL-10) cytokines by enzyme-linked immunosorbent assay. Both spontaneous and mitogen-induced cytokine production was measured. RESULTS: HIV infection was noted to have the following effects on cytokine production: (i) it led to the in vivo activation of type 2 cytokines in a small group of individuals with high CD4 numbers characterized by the spontaneous release of IL-4 and IL-10. Longitudinal data showed high spontaneous IL-4 and IL-10 to be a consistent feature of the patient group (at each timepoint some patients were high producers) but to be variable in a given individual; (ii) HIV infection impaired the ability of PBMC to respond to stimuli (selected for their ability to optimally induce each cytokine) in terms of IL-2, IL-4 and IL-10 production in patients with both high and low CD4 cell counts; and (iii) conversely, HIV infection led to an overproduction of IFN-gamma in patients with high CD4 counts; patients with low CD4 produced normal levels of IFN-gamma. CONCLUSIONS: Our observations did not suggest polarization of the type 1/type 2 cytokine profile in HIV patients. Instead, the data suggested more complex changes to type 1/type 2 cytokine patterns in HIV infection than originally proposed by the TH1/TH2 dichotomy.

CD4 Lymphocyte Count↗