November 2008

Claude MOLINA and Franz MARRACHE

• Therapeutic innovation in Asthma
• The beekeeper : a model of immunologic tolerance
• Is anti-fungal treatment useful in Severe Asthma with sensitisation to Fungi ?
• Mediterranean diet: Protective role for Wheezing in pre-school children ?

Therapeutic innovations in Asthma

1) Improvement of usual treatments
This excellent and comprehensive review (I. M. Adcock et al. New targets for drug development in Asthma. Lancet 2008; 372: 1073-1087) starts by highlighting that 90% of Asthma cases respond favourably to conventional therapy based upon inhaled corticosteroids and â2-agonists. Thus, the remainder consists of 5 to 10% of cases of severe Asthma, which are responsible for 50% of the costs associated with the disease and for which novel targets and new therapeutic approaches have to be developed. Monoclonal antibodies (mAb) have entered the therapeutic arsenal, with the anti-IgE Omalizumab which is successfully used in the severe allergic forms of asthma. However, research must understand the cellular and molecular mechanisms of these severe forms of Asthma, thereby suggesting the possibility of several different phenotypes of the disease.

The authors analyse the development of the ultra long acting â2-agonist, which may act rapidly, their effects lasting longer than 24h (carmoterol, indacaterol) and may be only taken once-a-day. Another approach is the attempt to avoid the side- effects of corticosteroids via the use of a pro-drug.
These ways include:
a) using the pro-drug which is only activated in the airways (ciclesonide)
b) dissociating corticosteroids from their different effects by modifying the activation of their receptor (transrepression)
c) by addition of a biochemical NO-donor group , which has been experimentally efficient
d) through utilisation of novel inhalers which deliver mono-dispersed particles with sparing effect, and equivalent efficacy.

One may also mention the anti-lipid mediator drugs such as anti-leucotrienes (Montelukast, Zileuton), not very effective but may eventually be tested in « neutrophilic » cases of Asthma since they inhibit neutrophil chemotaxis. Likewise,anti-prostaglandin PGD2 or anti-PAF drugs, are still at an experimental stage or at phase II of clinical trials. In any case, it is known that the inhibitory action upon a single mediator or receptor has little chances of being effective.

2) Therapeutic innovation in Asthma
The novel targets :
These are chemokines and their receptors, Th2-derived cytokines, transcription factors, enzymes and several immune cells. Chemokines are responsible for the recruitment of inflammatory cells into the airways. There are 4 families classified according to their cysteine radicals. Several receptors exist and one of them, CCR3 which recruits eosinophils is a preferential target .Their levels are increased in Asthma and inhibitory anti-sense oligonucleotides have already shown their efficacy in inhibiting eosinophil inflammation and bronchial hyperreactivity ( it is the case of TPI ASM8 from Topigen analysed in our February 2008 BUA).
However, other chemokines (CCL17, CCL22, CXCL8) may be important and their respective inhibitors are at an experimental stage or in phase II clinical trials.
Th2-derived cytokines have a role in chronic inflammation and airway modelling. If anti-IL-5 mAb have not been shown to be effective, blocking IL-4 and its á–subunit and IL-13 by Pitakinra (already mentioned in our BUA) has been shown to be an interesting approach, whereas anti-IL-13 as well as anti-IL-10 and anti-IL-12 mAb are currently being studied. Curiously, TNF-á has been shown to be a pro-inflammatory cytokine but its blockage was not associated with any clinical improvement of Asthma.
The authors also mention Suplatast tosilate which may inhibit IL-4 and IL-5 and has been slightly effective in a small clinical trial of moderate asthma.
Among the other targets
- phosphodiesterase inhibitors such as roflumilast and cilomilast, active by oral route, have side effects ,similar to those of theophylin, with nausea and vomiting;
- kinase inhibitors such as p38 MAPK, active by inhalation;
- transcription factors such as NFêB or IKK2 inhibitors useful in insensitive to corticosteroids asthma
- other nuclear factors such as PPAR (Peroxisome proliferator activated receptor) which, in association with corticosteroids may have an important anti-inflammatory role. Finally, the development of Immunotherapy targeting regulatory T cells (Treg) and Th17 cells, in combination with D3 vitamin and corticosteroids deserves to be mentioned.
This vast number of studies on biological or synthetic drugs, can be explained by the complexity of asthma mechanisms, but we must remind that targeting only one mediator, or receptor or enzyme is ineffective and meanwhile the development of distinct handprints of different subtypes of the disease, combination of therapies is clearly mandatory.

The beekeeper : a model of immunological tolerance
In an editorial in the Journal of Experimental Medicine (Published online November 10, 2008) Nicole Lebrasseur, quoting work from F. Meiler, observed with humour that better than a murine experimental model, the beekeeper fulfils an old Immunologist’s dream, by revealing that such an intrepid honey lover, kicks into action a group of T Lymphocytes which pass successively from an aggressive mode to a suppressive mode and vice-versa, just like Dr Jekyll and Mr Hyde.
In fact, due to the nature of their work, non allergic beekeepers receive when they collect honey, repetitive injections of high doses of bee venom antigens (a mean of 13 bee stings during the first week of the season is usual). In this 7 day period, the beekeepers develop tolerance which is associated with an inhibition of T cell responses, both in the skin (absence of late phase reaction) and in the blood (suppression of venom antigen-specific proliferation).

In fact, T cells which happily proliferate, in response to antigen, relax once the season starts and, instead of secreting Interferon-ã and IL 4 , by cytokine switch, start synthesising high levels of IL-10, which dampens immune reactions. These IL-10-producing regulatory T cells (Tr1) decrease the antigen-induced proliferation of other T cells in vitro. This T cell regulation continues as long as antigen exposure persists and return to in initial levels within 2 to 3 months after the season.

Such cytokine switch may require Histamine-related pathways; in fact, just like most allergens, bee venom sets off a release of histamine by mast cells and in vitro T cell studies show that the production of IL-10 and cell lethargy require the intervention of Histamine type 2 receptor (TGF-â does not seem to play an essential role in skin tolerance, in contrast with its action in mucosal tolerance).
It should be noted that such tolerance disappears at the end of the season, indicating a relatively transitory suppression of T cell activity. Afterwards, this cycle is repeated during the following season which allows one to reassure the beekeepers, if need be.

As far as bee venom-allergic individuals (who are generally deficient in IL-10) are concerned, there is no place for great enthusiasm about this finding since it shows that the success of allergen-specific immunotherapy entails a long and persevering maintenance of therapy.

Is Anti-fungal treatment useful in Severe Asthma with sensitisation to Fungi?
This is the question asked by the English authors from the University of Manchester as they analysed, in a randomised study, the response of asthmatic patients sensitised to one or various fungi, to Itraconazole (Randomized Controlled trial of Oral Antifungal treatment for severe asthma with fungal sensitization. D.W. Denning et al. Am.J.Resp.Crit.Care Med 2008, October 23).
58 subjets with severe asthma, treated with inhaled or oral corticosteroids (41% had already been hospitalised in the previous year) and having positive skin tests and/or specific IgE to one or various fungi: Penicillium, Candida, Cladosporium, Botrytis, Trychphyton, Alternaria, and Aspergillus (with the exception of subjets having precipitins against the latter) were recruited at 4 different hospitals. All the subjects had total serum IgE levels lower than 1000UI/ml.
Patients were treated either with Itraconazole orally (200mg/day) or with Placebo for 32 weeks and were subsequently followed for 16 weeks.
A standardised questionnaire with 32 items on Quality of Life of the asthmatic patient, followed by lung function testing, calculation of a rhinitis score and determination of total serum IgE levels were performed. Results were as follows:
At 32nd week, there was a significant improvement of the Quality of Life in nearly 2/3 of the cases (60%), when compared with the Placebo group. In fact, complete data were obtained from 41 subjects who have followed the treatment until the end of the study.
The Rhinitis score also improved, whereas it deteriorated in the Placebo group.
The levels of total serum IgE decreased significantly, dropping from 187 to 136 UI/ml, whereas they increased in the Placebo group, from 245 to 275 UI/ml.
Changes in lung function were modest: only morning peak expiratory flow significantly improved.
Overall, there were only a few cases of exacerbation of asthma (similar in both groups) which required an increase in the doses of corticosteroids or hospitalisation.
There were no severe side effects, but 7 subjects (5 of which were in the anti-fungal group) had to discontinue treatment.
The authors put forward some hypotheses to explain the favourable action of antifungal therapy (which progressively disappears after suspension of the latter): action on the eventual colonisation of airways by the fungi, synergy with corticosteroids, or direct stimulation of the immune system.

Mediterranean diet : Protective factor for Wheezing in pre-school children?
The Mediterranean diet (MD) is regarded in adults as protector for atherosclerosis and its cardio-vascular consequences. It is based upon increased ingestion of fruits and vegetables (anti-oxydants), n3- (fish oils) or n-6 (vegetable oil) polyunsaturated fatty acids, and a moderate ingestion of milk, meat, and avoidance of fast-food : hamburgers, fried foods, industrial cakes, pizzas…

A group of Spanish doctors had already shown that MD was a protective factor for allergy and asthma in children aged between 6 to 7 years (L. Garcia-Marcos et al. Thorax 2007; 62 : 503-508) and that, in contrast, obesity was a risk factor, particularly in girls. The same group (A. Castro-Rodriguez et al. J. Pediatrics 2008 ; 823-828) extended their epidemiological study to young children from 3 cities in the Southeast of Spain. They hand out questionnaires to the parents of 1784 children (mean age of 4 years), in searching children wheezing (asthma equivalent) in the previous year. The authors set up a score for MD according to the intake frequency of pro- and anti-MD foods.
A potent multivariate and logistic regression statistical analysis also incorporating family history of these children showed that, ingestion of Paracetamol, eczema, rhino-conjunctivitis and paternal asthma were significant risk factors for wheezing in children. In contrast, MD and the child’s older age were protective factors.

The authors acknowledge the difficulties in interpretation of these food questionnaires and cannot give advice on the amounts of such food necessary to ensure a protective effect. Therefore, they can only suggest a balance favouring pro-MD foods and pointing towards avoidance of risk foods.

Source: CEFCAP