April 2009
Claude MOLINA and Franz MARRACHE
- Is there a future for Mepolizumab in the treatment of Asthma?
- Exposure to Farms during Pregnancy and Infant Immunity
- Farmers, Atopy and the Lungs
- Allergy to Trichophyton and Asthma severity
- Zoology (Ants and Flies) to the rescue of Allergy
Is there a future for Mepolizumab (M) in the treatment of Asthma?
Two articles regarding to anti-IL-5 monoclonal antibody and eosinophil inhibitor: Mepolizumab (M) have been recently published, bearing in mind that previous research on its role in asthma had not been conclusive
The first one, from Canadian authors, is focused upon a relatively rare subgroup of corticoids-dependent asthma with sputum eosinophilia, and also aimed at analysing the corticoid-sparing effects of M. (P. Nair et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. NEJM 2009; 360: 985-93),.
In this randomised study, 9 patients, approximately 50 years old, were treated by perfusion of 750 mg M. once monthly for 5 months, 11 patients by Placebo.
At the end of this trial, only one of the patients treated, had an exacerbation of Asthma for 9 in the control group .
Moreover, M. had a significant corticoid-sparing effect and was associated with a clear decrease in blood and sputum eosinophilia, as well as improvement in FEV1, all symptoms maintained for 8 weeks after the last perfusion. The authors acknowledge the limited scope and the biases of this study, but they stress that it is a pilot one, useful for a specific category of Asthma.
The other article, from an English group (P. Haldar et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. NEJM 2009 ; 360 : 973-84) studied 61 individuals with this eosinophilic form of refractory asthma, and an history of recurrent severe exacerbations. In this randomised study, 29 patients were given a perfusion of 750 mg of M. every month for 1 year, and 32 were given placebo. The primary outcome measure was the number of exacerbations per subject during the year of treatment. Secondary outcomes included changes in asthma symptoms, quality of life scores (questionnaire), FEV1, bronchial reactivity and blood and sputum eosinophil counts. As in the canadian study, exacerbations were significantly less frequent in the group treated with M. In this latter, the numbers of blood and sputum eosinophils decreased, quality of life improved and even in some cases, the bronchial wall thickness, as measured by scanner, was reduced.
M. was well tolerated but had no effect upon respiratory function or bronchial reactivity (which proves the dissociation between eosinophilic inflammation and bronchial hyperreactivity or respiratory function in asthma). Thus, these 2 studies are in agreement as they conclude that M. should be reserved for a particular and rare phenotype of Asthma: an asthma which tends to clearly progress, difficult to treat and associated with eosinophilia.
Exposure to Farms during Pregnancy and Infant Immunity
Several studies have shown that living on farms during pregnancy decreases the risk of allergy for the child, although the immunological mechanism of this protective effect has not been elucidated. The work by the Munich group headed by Erika Von Mutius has focused upon this problem (B. Schaub et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. JACI 2009; 01.56 DOI)
84 pregnant women were recruited before delivery, and questionnaires focusing on conditions of exposure to farm environments were applied (22 women lived on farms + 2 excluded and 60 were controls). Cord blood was taken upon delivery and stimulated with a microbial peptidoglycan (Ppg), a mitogen (PHA: glucidic fermentation polyester of bacterial source), House dust mite allergen extracts (Der p1) and combinations of these stimuli.
Regulatory T cells (Treg) were then examined in terms of proliferation, (expression of CD4 CD25, FOXP3 and intracellular expression of lymphocyte activation gene 3), as well as production of Th1 and Th2 cytokines, and IL-17.
The numbers of Treg were significantly increased in farmer women (with or without PHA stimulation) and were associated with an increase in the level of expression of FOXP3 (after stimulation with Der p1 and Ppg) and augmented expression of lymphocyte activation gene 3.
The functional activity of Tregs was also increased, whereas the levels of Th2 cytokines (IL-5) were lower and the level of IL-6 was higher. Furthermore, the greater the number of stables animals present on the farm, the more apparent did the effects upon Treg, or upon Th1 and Th2 cells, become.
In conclusion, exposure to a farm during pregnancy increases the number and function of regulatory T cells and decreases secretion of Th2 cytokines.
Thus, farm exposure would represent a natural model of immunotherapy, including a selection of immunostimulants in association with allergens, and a modulation of the immune system of the infant since birth.
It should also be stressed that, although being raised on a farm is beneficial for neonates, this is not always the case for adults exposed to various pollutants in their professional environment which also depends upon the type of their occupational-related activities.
Farmers, Atopy and the Lungs
This very important work by a Norwegian team (W. Eduard et al. Chronic bronchitis, COPD and Lung Function in Farmers. Chest 2009; 03 06 early 08-2192) draws one’s attention upon occupational environmental risks in farmers, by discriminating between livestock farmers ( raising animals such as cattle, swine, poultry) and crop farmers .
4735 individuals were studied out of a cohort of 8482 farmers. The authors stressed that the risks of asthma were more frequent in such a population, although smoking habits were less frequent than the European average and that, as it is known, living on a farm is supposed to protect the child against manifestations of allergy.
The individuals were followed up between 1992 and 1996. 1213 among them tested positive for atopy (skin prick tests and IgE).
A particularly detailed study of the different types of exposure of these farmers to environmental pollutants was carried out by careful techniques: dusts, fungi, actinomycetes, endotoxins, storage mites, bacteria, but also inorganic dusts, silicium, ammonia and SH2. The level and mean duration of exposure for each farmer was calculated in terms of hour per year in 127 farms selected by randomisation.
The cases of asthma were diagnosed by the doctor, chronic bronchitis (CB) was diagnosed on the basis of the presence of cough and sputum production for at least 3 months per year during the previous 2 years. Diagnosis of COPD (Chronic Obstructive Pulmonary Disease) was complemented by lung function testing.
In comparison with those crop farmers, there was a higher percentage of livestock farmers with CB and COPD, as reflected in a clearly lower FEV1, without differences in FVC (Forced Vital Capacity).
Atopic farmers had a significantly lower FEV1 than non-atopic farmers, but atopy was not directly linked to CB OR COPD or FVC.
COPD was strongly associated with overall rural exposure, particularly among livestock farmers, and was related to the duration and type of exposure as well as atopic background.
It should be stressed that although ammonia, SH2 and inorganic dust clearly have detrimental respiratory effects, biological agents have a very important aetiological role and atopic farmers are more prone to developing pathological reactions than non-atopic farmers.
Allergy to Trichophyton and Asthma severity
The association between fungi allergy and asthma is not rare ; it is often regarded as of secondary importance, particularly if it manifests only by positive skin prick tests. On the other hand, the validity of anti-fungal treatment in this context is far from established (see November 2008 ABA). In this article by Japonese authors from Kyoto and Osaka (H. Matsuoka et al. Specific IgE response to Trychophyton and asthma severity. Chest 2009; 135: 898-913) allergy is confirmed by the presence of a relatively high level of IgE specific for a fungus that usually colonises skin lesions: Trychophyton.
It is practically the only microorganism responsible for dermatophyte infection in Japan, and the authors had detected it in a limited number of cases of asthma, in skin tests and bronchial provocation tests that were positive for this fungus. In fact, in a previous study, anecdotal evidence was shown that an anti-fungal treatment with Fluconazole(®) had a corticosteroid-sparing effect and had been associated with a decrease in bronchial hyperreactivity. The authors then decided to carry out a more important trial.
258 asthmatic individuals were subdivided into 3 groups: 123 cases of Mild Asthma, 101 cases of Moderate Asthma, and 34 cases of Severe Asthma. The study also included 114 healthy controls. Besides common aeroallergens, all individuals were screened for Trychophyton rubrum–specific IgE, with positive levels estimated between 0.35 and 100 U/ml.
The levels of T. Rubrum-specific IgE were significantly higher in patients with Moderate Asthma when compared to healthy controls (15.8% versus 7%; p=0.04) and patients with Mild Asthma (4.9%; p=0.006). These levels were also significantly higher in patients with severe asthma (32.4%), when compared to healthy controls (p=0.0001) or to patients with mild asthma (p ≤ 0.0001) or even with Moderate asthma (p= 0.04). In contrast, there was no significant difference in these levels between patients with Mild asthma and healthy controls.
The levels of positivity for the other aeroallergens (cat, dog, grass pollens, fungi) were higher in asthmatic patients than in healthy controls but there were no differences between the 3 groups of asthmatic patients.
Given that 52 individuals who were simultaneously positive to T. rubrum and other fungi were excluded from the statistical analysis, allows the authors to conclude that there was no cross-reactivity between these allergens and T. rubrum.
Thus, T. rubrum–specific IgE levels are an independent factor of severity of asthmatic disease.
The mechanism of this respiratory allergy to a skin fungus remains obscure, since the authors negate the role of immuno-depression, sometimes observed with prolonged treatment with corticoids. They rather suggest a dermal and inhalational absorption of the fungal allergen. Is this due to a certain geographical specificity related to the country of the Rising Sun?
Zoology (Ants and Flies) to the rescue of Allergology
The review “Nature” published an article by E.C. Hayden on the antibiotic and antifungal effects of a type of “leaf cutting” ants from Central America, which seem to be a real moving pharmaceutical factory (Fungus Farmers show way to new drugs. Nature News. 29 Mars 2009).
In fact, these ants do not feed on leaves, which they use for their garden nests, but rather on mushrooms that grow in the latter. And, as shown by R. Currie 10 years ago (Nature 1999 ; 398 : 701-704 ), these ants are host to colonies of actinomycetes which release an antibiotic which protects these mushrooms from other parasitic mushrooms. One of these antifungals called dentigerumycin inhibits the growth of Candida albicans, whose pathological role is known, namely in allergy.
However, this finding is equally interesting for the research for new antibiotics and also for the development of biofuels since some types of these fungi can degrade cellulose, thereby allowing the production of biofuels more active than those obtained from maize, for instance.
As far as Drosophila flies (fruit flies) are concerned, they are already used in human genetics for research on chromosomes and mutations. These flies can also yield very useful information for research in asthma (T. Roeder et al. Drosophila in asthma research. AJRCCM 2009; 2 April; in press).
Although the type of animal mainly used in asthma research are transgenic mice, Drosophila seems to be a less complex model. Its advantages are of 2 types: a) there is no adaptive immunity in Drosophila, only innate immunity; b) most of the genes are located, just like in Man, within epithelial cells in the respiratory system which in itself is similar, in its simplified structure, to that of Man (with the exception that it has no ciliary or oxygen transportation functions).
Finally, the concurrent study of the human genome and the relationships that are beginning to be studied between gene and function, allow one to predict important advances in knowledge regarding the known repertoire of numerous genes that predispose to asthma. The authors mention, as examples of genes that are homologous between Man and Drosophila those of Toll-like receptors, Serpines (serine protease inhibitors) or even those of adrenergic receptors.
Novel, very sophisticated, biological technologies may yield significant progress in the analysis and comprehension of a disease as complex as asthma.
Source: CEFCAP
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