Biomedical subjects
Graham A W Rook
Publications and source records attributed to Graham A W Rook.
Increased expression of mRNA encoding interleukin (IL)-4 and its splice variant IL-4delta2 in cells from contacts of Mycobacterium tuberculosis, in the absence of in vitro stimulation.
Expression of interleukin (IL)-4 is increased in tuberculosis and thought to be detrimental. We show here that in healthy contacts there is increased expression of its naturally occurring antagonist, IL-4delta2 (IL-4delta2). We identified contacts by showing that their peripheral blood mononuclear cells (PBMC) released interferon (IFN)-gamma in response to the Mycobacterium tuberculosis-specific antigen 6 kDa early secretory antigenic target (ESAT-6). Fresh unstimulated PBMC from these contacts contained higher levels of mRNA encoding IL-4delta2 (P=0.002) than did cells from ESAT-6 negative donors (noncontacts). These data indicate that contact with M. tuberculosis induces unusual, previously unrecognized, immunological events. We tentatively hypothesize that progression to active disease might depend upon the underlying ratio of IL-4 to IL-4delta2.
Oral treatment with SRP299 (killed Mycobacterium vaccae) inhibits experimental periodontal disease in Wistar rats.
OBJECTIVE: Mycobacterium vaccae injected subcutaneously was previously shown to prevent and treat ligature-induced periodontal disease (PD) in Wistar rats (Breivik & Rook 2000, 2002). Since mycobacteria are readily taken up via Peyer's patches in the intestine, we have now tested the ability of oral SRP299 (killed M. vaccae) to prevent ligature-enhanced PD in Wistar rats, and to modulate the accompanying cytokine and corticosterone responses. MATERIAL AND METHODS: A single oral dose of SRP299 (1 mg) was given 14 days before the application of ligatures. PD was assessed when the ligatures had been in place for 56 days. RESULTS: Oral SRP299 reduced bone loss (p = 0.036, X-ray; p = 0.061, histometry) and fibre loss, both on the ligatured (p = 0.0047) and control (p = 0.005) sides, and also reduced the level of TNF-alpha (p = 0.0137) and corticosterone (p = 0.048) induced by intraperitoneal endotoxin lipopolysaccharide (LPS). CONCLUSIONS: SRP299 administered by the oral route diminishes ligature-induced bone and fibre loss in this model. This effect may be attributable to the known ability of SRP299 to evoke regulatory T cells, although the mechanism could not be investigated in this study. Treated rats also had less excitable hypothalamo-pituitary-adrenal (HPA) axes. HPA axis overactivity is a known risk factor in human PD. Trials of SRP299 in human PD are now justified.
Innate immune responses to mycobacteria and the downregulation of atopic responses.
PURPOSE OF REVIEW: Exposure to certain environmental microorganisms can promote the induction of T regulatory cells via the innate immune system. This review explores the possibility that reduced exposure to such organisms is leading to increased immunoregulatory disorders in a subset of individuals in whom this regulatory T-cell-inducing pathway is less efficient. We concentrate on mycobacteria and on asthma, because these are well documented. RECENT FINDINGS: The blood cells of the children of farmers, who are partly protected from allergies, express increased levels of messenger RNA encoding CD14 and TLR2, and polymorphisms of CD14 are linked to allergic manifestations in some studies. Polymorphisms of TLR2 (which recognizes mycobacterial components in concert with CD14) are involved in the pattern of response to mycobacteria, and in the type of leprosy that develops. Similarly, polymorphisms of Nramp1, which affect the response to mycobacteria, are linked with the diseases of immunodysregulation that are increasing in parallel with allergic disorders. Moreover, congenic mice bearing different variants of Nramp1 differ in their allergic responses. These parallels are suggestive, in view of the observation that a saprophytic environmental mycobacterium is a potent inducer of regulatory T cells, and has shown significant effects in several phase I/II studies in man. SUMMARY: The components of the innate immune system that are involved in responses to mycobacteria overlap with those implicated in allergic disorders. Polymorphisms might define the subset of individuals who develop immunoregulatory disorders. Understanding the role of the innate immune system will facilitate the design of clinical trials using microbial products.
Immunotherapy with mycobacteria.
PURPOSE OF REVIEW: To summarize and evaluate critically recent progress with mycobacteria as a potential novel disease modifying treatment strategy in asthma. RECENT FINDINGS: The link between exposure to pathogenic or saprophytic mycobacteria and protection from allergic diseases is still controversial, and recent epidemiological studies, which addressed only exposure to Mycobacterium tuberculosis or bacillus Calmette-Guérin, did not help to clarify this issue. Moreover, the clear efficacy of mycobacterial treatment seen in animal models has not been reproduced in human asthma, and a recent small study testing the hypothesis that heat-killed Mycobacterium vaccae attenuates asthmatic reactions after allergen challenge did not provide convincing results. However, it has been shown that treatment of mice with M. vaccae induces the generation of allergen-specific T regulatory cells capable of suppressing allergen-mediated eosinophilic lung inflammation, suggesting that a general deficiency of T regulatory cell activity might be responsible for the increased prevalence of asthma. This hypothesis is supported by findings that a lack of T regulatory cells, as found in genetic disorders of man and mouse attributable to a mutation of Foxp3, a transcription factor specifically expressed by T regulatory cells, is associated with manifestations of severe atopy and autoimmunity, precisely the spectrum of diseases linked to the hygiene hypothesis. SUMMARY: Further studies on the relationship between mycobacteria and atopic disorders are needed, but there is reason to believe that the novel findings and molecular mechanisms associated with mycobacterial infections will further strengthen the currently unproved therapeutic value of immunotherapy with mycobacteria.
The importance of models of infection in the study of disease resistance.
Models currently occupy the crucial first step in the research flow for the development of new drugs and vaccines. Some animal models are better at reflecting the host-pathogen interaction in humans than others; this depends on the pathogen and its host specificity. Data gathered from what are often poorly adapted models provide a mosaic of sometimes contradictory information, yet there is little incentive to better delineate the relevance of models or to exploit recent advances to develop improved ones. This review reports on three particularly intractable human pathogens - Mycobacterium, Plasmodium and Schistosoma - and reflects that the extent to which these model systems mimic infection and protection processes in humans might not be sufficiently well defined.
Can nerve damage disrupt neuroendocrine immune homeostasis? Leprosy as a case in point.
The crucial clinical problem in leprosy is the occurrence of acute inflammatory episodes that lead to nerve damage, even after the infecting organisms have been killed by antibiotics. We suggest that the instability of these inflammatory sites is attributable to a disturbance of the role that nerves play in the regulation of inflammation. The destruction of sensory C fibers and sympathetic innervation will remove anti-inflammatory feedback circuits. Moreover, diminishing levels of neuropeptides and changes in the cytokine profile will affect the cortisol-sensitivity of infiltrating T cells, and modulate the cortisol-cortisone shuttle so that the inflammatory site becomes resistant to physiological levels of anti-inflammatory adrenocortical steroids.
Dangers of therapeutic manipulation of the Th-Th2 balance.
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Treatment with SRL172 (heat-killed Mycobacterium vaccae) inhibits progression of established experimental periodontal disease in Wistar rats.
Periodontal disease is accompanied by a change in the periodontal bacterial flora, and an increase in Th2 cytokine expression. Therefore, preparations that can down-regulate Th2 responses and increase Th1 responses to bacteria may have therapeutic effects. SRL172, a preparation of heat-killed Mycobacterium vaccae (NCTC11659), has been shown to have these properties in man and animals and, in a previous study, a single subcutaneous injection of this material 13 days before application of ligatures to the right second molars of Wistar rats strikingly reduced subsequent destruction of the tooth-supporting tissues. The same material has therefore been tested in a therapeutic protocol, in rats with ongoing periodontal disease. A silk ligature was placed round the maxillary right second molar in the gingival sulcus on day 0. This was removed after two weeks, and the animals immediately received 0.1 mg SRL172 s.c. or saline. One week later (i.e. at three weeks), a boost of 1.0 mg SRL172 or saline was given. Animals were sacrificed at eight weeks (i.e. five weeks after the booster dose). Treatment of ongoing periodontal disease with SRL172 significantly reduced fibre loss (p = 0.046 by histometry) and bone loss (p = 0.0008 by radiography) on the ligatured side, and reduced fibre loss (p = 0.0086) on the control side. Thus SRL172 is an effective treatment in this model. As SRL172 has undergone extensive safety testing in man, these results justify clinical studies in periodontal disease, and such studies are now planned.
Give us this day our daily germs.
Are we sparing the dirt and spoiling our children's immune systems? The theory that some germs are necessary in developing healthy immune systems is gaining credence as more evidence emerges. It is vital that we find out which germs are needed, when and how, before the increase in diseases attributable to faulty regulation of the immune system (allergies, autoimmunity, inflammatory bowel disease) spirals out of control.