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: 21/07/98
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| New
therapeutic approaches for allergic diseases of
the respiratory tract |
Nouvelles
approches thérapeutiques pour le traitement des
affections allergiques des voies aériennes |
Paris,
April 1 - 4, 1998
Chairpersons : Stephen
T. Holgate (University of Southampton,
Southampton, United-Kingdom), Charles Naspitz (Escola
Paulista de Medicina, Sao Paulo, Brazil), B.
Boris Vargaftig (Institut Pasteur,
Paris, France)
Preceded on April 1 (5-7 p.m.) by a
" Perspectives of Allergy " Symposium on "
Rhinitis: mechanisms and management "*
chaired by Bernard David (Institut Pasteur,
Paris, France) and Steven R. Durham (Imperial College
School of Medicine, National
Heart & Lung Institute, London, United-Kingdom)
Speakers: P. Howarth (U.K.):
Pathophysiology of rhinitis: rationale approach to
therapy - S. Durham (U.K.): Allergen avoidance and
immunotherapy - G. W. Canonica,(Italy): Antihistamines:
efficacy and safety - N. Nygink (DK): Topical
corticosteroids: What’s new? - S. Durham (U.K.):
Panel discussion: rhinitis guidelines.
* Sponsored/Soutenu par by the  International
Association of Allergology and Clinical Immunology,
through an educational grant provided by Hoechst Marion
Roussel
and followed on the morning of April 4 by
a Satellite on " Progress in Molecular Diagnostics
of Allergy " chaired by G. Peltre (Institut Pasteur,
Paris, France)
Institut
Pasteur, Paris, France.
Contact : Ludovic Drye, Institut Pasteur,
C.I.S., 28 rue du Docteur Roux, 75724 Paris Cedex 15
France
Fax 33 1 40 61 34 05 - E.mail : l. Drye
http://www.pasteur.fr/Conf/euroconf.html
October 15-17 1997 : EuroConference
on Cytokines
( http://www.asmanet.com/cytokine.html
)
April 1- 4 1998 : EuroConference
on New Therapeutic Approaches for
Allergic Diseases of the
Respiratory Tract ( http://www.asmanet.com/allergic-diseases.html
)
...
|
| |
PRESENTATION
| Allergic diseases of the human
respiratory tract, mainly asthma, are among the most
common chronic diseases and are responsible for a large
amount of health care spending. For yet unknown reasons,
their prevalence, already high, is increasing in most
countries. Since the development of topical
corticosteroids, few important discoveries with
therapeutic implications for those diseases have been
made. By contrast, important progresses were obtained in
the recognition of the inflammatory and immunological
components of the allergic response as the basis for the
different functional and structural changes in the
airways. This Institut Pasteur Euroconference will
review the economy, the epidemiology and physiopathology,
the role of lipid mediators and cytokines, of lymphocytes
and eosinophils, the neural control of the airways, the
role of adhesion molecules, the role of inhaled
substances (allergens, endotoxins).
Emphasis will be made on therapeutical consequences.
Indeed, the increasing knowledge of this complex
multifactorial interaction should lead to the development
of new therapeutic interventions and to a better
understanding of the mode of action of the classical
treatments. This Conference will provide a comprehensive
and up-to-date overview of this fascinating field and of
its pharmacological and therapeutic implications.
|
Les maladies
allergiques des voies aériennes, particulièrement
l’asthme, comptent parmi les maladies les plus
répandues et sont responsables d’un coût
médico-social considérable. Pour des raisons mal
comprises, leur prévalence, déjà élevée, augmente
dans la majorité des pays. Peu d’innovations
thérapeutiques ont suivi l’introduction des
glucocorticostéroïdes d’action locale, mais des
progrès considérables ont été effectués dans la
compréhension des mécanismes inflammatoires et
immunologiques de la réponse allergique, en tant que
substrat pour les modifications fonctionnelles et
structurelles des voies aériennes. Cette
EuroConference de l'Institut Pasteur sera l’occasion
de revoir l’épidémiologie et la physiopathologie,
le rôle des médiateurs lipidiques et des cytokines, des
lymphocytes et éosinophiles, la modulation nerveuse des
voies aériennes, le rôle des protéines
d’adhérence et des substances inhalées,
allergènes et endotoxines.
La reconnaissance croissante de ces interactions
complexes, devra permettre le développement de nouvelles
modalités d’intervention thérapeutique et une
meilleure compréhension du mode d’action des
traitements connus. Cette Conférence assurera ainsi une
revue générale et globale du sujet, notamment de ses
implications pharmacologiques et thérapeutiques.
|
Wednesday April 1, 1998
04:00 - 05:00 p.m.
Registration of the participants (I)
Thursday April 2, 1998
7:45 - 8:25 a.m.
Registration of the participants (II)
8:25 - 8:30 a.m.
Presentation of the Euro Conferences by B.
Boris VARGAFTIG, Member of the Board of Directors, Institut
Pasteur, Paris, France
8:30 - 9:10 a.m.
The roots of respiratory allergy in early life.
Dramatic increases have been recently observed in the prevalence
of respiratory allergies, especially in developed countries.
Recent evidence also suggests that in most cases of respiratory
allergies, symptoms initiate very early in life. It is thus
likely that recent environmental changes which affect very young
children may be responsible for those increases in prevalence.
Paradoxically, infant morbidity and mortality are at their lowest
levels ever, and standards of preventive care for common
respiratory diseases in childhood are almost invariably excellent
in developed countries. Primary prevention of this new breed of
common illnesses is a major challenge for medicine in the 21st
century.
Fernando
D. Martinez
The University of Arizona
Tucson, AZ, USA
Introduction to immune mechanisms
9:10 - 9:40 a.m.
lmmunologic Targets for Therapeutic Interventions.
Recent research has emphasised the importance of immune deviation
of T cells in the Th-2 mediated inflammatory response of chronic
mucosal allergic disease. Dendritic cells as professional antigen
presenting cells are particularly important. The mechanisms
involved in antigen processing, cytokine production and the
critical requirement for co-stimulatory molecules such as B7/CD28
will be discussed in relation to new targets for therapeutic
intervention in the initiation and propagation of the chronic
inflammation response. Finally reference will he made to the
inflammatory repair cycle and the role of the epithelium,
endothelium and fibroblasts in providing additional signals that
enhance disease progression.
Stephen
T. Holgate
University of Southampton
Southampton , U.K.
9:40 - 10:10 a.m.
| Epidemiology of respiratory allergic
diseases. The prevalence of asthma is as high as 8
to 10% in adults, 10 to 15% in childhood; the prevalence
of rhinitis is up to 20%; the prevalence of atopy, as
assessed by at least one positive skin prick test to
aeroallergen, appears to be as high as 40 or 45%. The
prevalence of allergic respiratory diseases is increasing
and is doubling every 10 years. There is difference
between countries but the rate of increase seems to be a
general situation. Most of the authors hypothetize that
environmental factors explain mainly this phenomenon.
There are several hypothesis: infection, pollution,
indoor pollution. Our knowledge has to increase rapidly
in order to propose a better primary prevention to our
patients and their family.
|
Epidémiologie
des maladies allergiques respiratoires. La
prévalence de l'asthme est d'environ 8 à 10 % chez
l'adulte et 10 à 15% chez l'enfant ; celle de la rhinite
est de 20 % et celle de l'atopie (évaluée par un test
cutané positif pour au moins un allergène de
l'environnement) de 45 %. Cette prévalence augmente et
double tous les 10 ans. Il y a des différences
régionales, mais l'augmentation semble être un
phénomène général. La plupart des auteurs estiment
que les facteurs environnementaux expliquent ces
données. Plusieurs hypothèses ont été proposées:
infection, pollution, pollution intérieure. Nos
connaissances doivent s'améliorer rapidement pour
pouvoir proposer des mesures de prévention primaire à
nos malades et leur famille.
|
Philippe
GODARD
Hôpital Arnaud de Villeneuve
Montpellier, France.
10:10 - 10:30 a.m.
Coffee Break
10:30 - 11:10 a.m.
Differing patterns of T-cell memory development against
inhaled allergens in atopics versus normals: implications for the
design of new prophylactic and therapeutic strategies.
T-cell priming against ubiquitous inhalant allergens commonly
occurs during late intrauterine life. These responses are
subsequently reshaped by direct postnatal exposure to allergens,
particularly between birth and age 5yrs, resulting in either
further boosting of Th2 immunity, immune deviation towards the
Thl compartment, or (less commonly) development of
unresponsiveness via T-cell deletion/anergy. The efficiency of
selection against Th2 memory appears related to the kinetics of
postnatal maturation Thl -associated immune functions, at the
level of the T-cell compartment itself and/or the APCs. These
findings point to a potential prophylactic/therapeutic "
window " in early life, that may afford novel opportunities
for primary prevention of allergic respiratory diseases.
Patrick
G. Holt
TVW Telethon Institute for Child Health Research
West Perth, Western Australia.
Genetics and antibodies
11:10 - 11:40 a.m.
Genetics and gene discovery.
Asthma and atopy are familial. Susceptibility to these illnesses
is due to genetic factors interacting with the environment.
Identification of the genes underlying asthma will lead to
improvements in the diagnosis and classification of the disease.
Genetics will distinguish targets for focussed drug development
and effective therapy of asthma. Identification of genetically
susceptible infants will make possible the prevention of disease.
A number of genes have already been identified contributing to
the asthmatic state: these include the Fc[epsilon]RI-[beta], TNF,
HLA-DR and TCR a loci. Positional cloning methods are now being
used in an international effort to identify all the major genetic
influences on asthma.
William
Cookson (see also http://www.medicine.ox.ac.uk/~.awalley.ndm.medicine/cookson.htm
)
University
of Oxford - John Radcliffe Hospital
Oxford, U.K.
11:40 - 12:20 p.m.
Anti-Ige Treatment of Allergic Airway Disease.
Antigen binding to IgE on mast cells in the respiratory tract is
thought to trigger the release of mediators responsible for the
early, and possibly also the late response to allergen challenge.
To examine the possible clinical benefit of reducing levels of
IgE, the effects of treatment with a monoclonal,
non-anaphylactgenic anti-IgE antibody directed against the region
on the Fc portion that binds to Fc[epsilon]R1 and Fc[epsilon]R2
receptors. Treatment with this anti-IgE Mab reduced serum IgE to
undetectable levels and markedly reduced not only the immediate
bronchoconstriction provoked by allergen challenge in asthmatic
subjects, but the late response as well. Trends toward reductions
in antigen-induced sputum eosinophilia and bronchial
hyper-reactivity were also apparent. Studies of the effects of
anti-IgE treatment in murine models of allergic inflammation
suggest that the reduction in the late response and in airway
eosinophilic inflammation may be due to inhibition of
IgE-focusing of antigen presentation to Th2 cells, rather than to
inhibition of mast cell activation. Trials of the clinical
efficacy of anti-IgE treatment in chronic severe asthma are now
on-going .
Homer
A. Boushey
Asthma Clinical Research Center
University of California,
San Francisco, CA, USA
12:20 - 12:25 p.m.
Group photo
12:25 - 01:45
p.m. Lunch
01:45 - 02:15 p.m.
Small molecule antogonists of a4 integrins: novel drugs for
asthma.
The integrin a4b1 is a heterodimeric cell surface molecule
central to
leukocyte-cell and leukocyte matrix adhesive interactions. We
have designed
selective a4 integrin small molecule antagonists, some with
subnanomolar
potencies in vitro. These molecules are efficacious in vivo in
both murine and sheep models of allergic asthma. One compound,
designated BIO1673, has steroid-like properties in the sheep
model. It has been selected as a clinical candidate and its
efficacy will be evaluated in human asthmatics in the near
future.
Roy Lobb
Biogen Inc.
Cambridge, MA, USA
Pharmacological management (I)
02:15 - 02:45 p.m.
| The Role of Antihistamines in the
Management of Respiratory Allergy. Antihistamines
(Hl-receptor antagonists) play a major role in the
treatment of allergic rhinitis. They work primarily by
blocking the effects of histamine at Hl receptors on
precapillary venules and on sensory nerves, and by
relieving rhinorrhea, sneezing, and nasal itching, but
not congestion. Although old and new Hl-antagonists
generally have similar efficacy, the latter are less
likely to cross the blood-brain barrier, block the
neurotransmitter effects of histamine in the central
nervous system, and produce somnolence or impair
performance. Rarely, astemizole or terfenadine may
prolong the QTc interval and cause cardiac arrhythmias.
In contrast to their important role in allergic rhinitis
treatment, in chronic asthma treatment, H l-antagonists
have a minimal beneficial effect.
|
Le rôle des
antihistaminiques dans les maladies respiratoires
allergiques. Les antihistaminiques
(antagonistes des récepteurs H1) jouent un rôle majeur
dans le traitement de la rhinite allergique. Ils agissent
essentiellement en bloquant les effets de l'histamine sur
les récepteurs H1 au niveau des vénules précapillaires
et des nerfs sensitifs et réduisent ainsi la
rhinorrhée, les éternuements et les démangeaisons
nasales sans néanmoins affecter la congestion. Même si
des antagonistes anciens ou plus récents montrent des
effets similaires, ces derniers croisent moins la
barrière hémato-encéphalique et interagissent moins
avec les effets de l'histamine en tant que
neurotransmetteur dans le système nerveux central; ils
induisent ainsi moins de somnolence et affectent moins
les performances. Rarement, l'astemizole ou la
terfenadine peuvent prolonger l'intervalle QTc et
provoquer des arythmies cardiaques. Contrairement à leur
rôle dans le traitement de la rhinite allergique, les
antagonistes H1 n'ont qu'un effet marginal dans l'asthme
chronique.
|
F. Estelle R. Simons
The University of Manitoba
Winnipeg, Canada
02:45 - 03:15 p.m.
Beta agonists: present use and controversies.
Beta agonists are the oldest, over 5000 years ago with the
Chinese herb " ma huang ", and the most widely used
drugs for the treatment of asthma. Despite this, several
controversies continue regarding its use. Questions regarding
daily use, development of tolerance, use at stoichiometric
isomers, effects on the development of increased bronchial
hyperreactivity and specific drug versus class effects are raised
in the literature regularly. This presentation will attempt to
raise these issues for further discussion and thougth.
David
G. Tinkelman
National
Jewish Medical and Research Center
Denver, Colorado, USA.
03:15 - 03:30 p.m.
Tea break
03:30- 04:00 p.m.
Muscarinic receptor subtypes in airways.
Anticholinergic drugs are the most effective bronchodilators
in COPD as vagal cholinergic tone is the only reversible element.
These drugs block muscarinic receptors of which three subtypes in
human airways. Bronchoconstriction and mucus secretion are
predominantly mediated via M3 receptors and to a
lesser extent by M1 receptors in parasympathetic
ganglia. M2 receptors on cholinergic nerve terminals
act as feedback inhibitory receptors for acetylcholine release.
Non-selective anticholinergics, such as ipratropium bromide
inhibits M2 as well as M3 receptors and may
therefore increase acetylcholine release and be less effective
that M3-selectiove inhibitors. The most promising drug
in development is tiotropium bromide which has a unique kinetic
selectivity for M1 and M3 receptors. It
dissociates rapidly from M2 receptors but has a very
long action on M1 and M3 receptors, In
clinical studies inhaled tiotropium gives bronchodilatation and
protects against bronchoconstriction for up to three days after a
single dose. It is proving to be very effective as a once daily
bronchodilator in COPD.
Peter
J Barnes
Department of Thoracic Medicine
National Heart
& Lung Institute
London, U.K.
Pharmacological management (II):
04:00 - 04:40 p.m.
Phosphodiesterase Type 4 as a Target for treating Asthma.
The predominant cyclic AMP phosphodiesterase (PDE) present in
tissues involved in allergic diseases of the airways, is PDE type
4. Elevation of cAMP by selective PDE4 inhibitors relaxes airway
smooth muscle, prevents the release and synthesis of
bronchoconstrictor mediators, suppresses inflammatory leukocyte
activation, inhibits cytokine synthesis and reverses neuronal
hyperresponsiveness. In an antigen-provocation study in human
asthma, the novel selective PDE4 inhibitor CDP840 significatly
reduced the late phase response. This result indicates that PDE4
inhibitors could have therapeutic value in the prophylactic
management of asthma.
Gerry
A. Higgs
Celltech Therapeutics Ltd
Slough, Berkshire, U.K.
04:40 - 05:20 p.m.
New targets using Thl/Th2 balance.
The commitment of naive cells to the Th2 phenotype appears to
play an important tole in the pathogenesis of allergic disease on
the basis of this subset of cells to secrete IL-5 which is
essential for eosinophil mobilisation and IL-4 which is required
for B cell switch to IgE secretion. This presentation discusses
the involvement of various molecules including cytokines (IL-4,
IL-12), costimulatory molecules (B7-1 and 2, CD40) and
transcription factors (GATA-3) that may play a role in regulating
both the differentiation and activation of Th2 cells.
Anthony J. Coyle
Millennium Pharmaceuticals Inc.
Cambridge, MA, USA
05:20 - 06:00 p.m.
| Is Interleukin-5 a therapeutic target
in allergic diseases of the airways ? Interleukin-5
is the most specific and effective cytokine accounting
for eosinophil differentiation and maturation. Its gene
expression and protein production are usually increased
in severe allergic conditions. IL-5 induces bone marrow
eosinopoiesis, but does not affect directly airways
reactivity, a feature which might have been expected if
eosinophils and hyperreactivity were directly associated.
Since transgenic animals for IL-5 are not turned
allergic, it is likely that IL-5 may be essential for
eosinophil-smooth muscle interactions, but that other
factors are required, such as increased IgE titres.
Strategies for reducing IL-5 and related factors, as well
as in vitro and in vivo models for the study of the role
and of modulation of IL-5 will be reviewed.
|
L'Interleukine-5
en tant que cible dans les maladies allergiques des voies
aériennes. L'Interleukine 5 est la cytokine
la plus spécifique et efficace pour induire la
différenciation et la maturation des éosinophiles.
L'expression de son gène et la production de la
protéine sont souvent augmentées dans les maladies
allergiques. L'IL-5 induit l'éosinopoïèse dans les
organes hématopoïètiques, mais n'affecte pas
directement la réactivité des voies aériennes, ce qui
serait attendu si les éosinophiles induisaient
directement l'hyperréactivité bronchopulmonaire.
Puisque les souris transgéniques pour l'IL-5 ne sont pas
rendues allergiques, il est clair que d'autres facteurs
sont nécessaires, comme une augmentation des titres en
IgE. Les stratégies pour réduire l'IL-5 et les facteurs
associés, ainsi que les modèles in vivo et in vitro les
plus employés seront discutés.
|
B.
Boris Vargaftig
Pharmacologie cellulaire
Institut Pasteur
Paris, France
Friday April 3, 1998
8:30 - 9:00 a.m.
Socio economics of asthma.
The morbidity of asthma is also accompanied by socio economic
costs. Poorly treated asthma is a burden on society as well as
the patient. The social impact can be great in terms of the of
the patient and family and the financial costs of asthma fall not
only on patient and family but also on society through high
health care costs. The major direct costs are hospital admissions
and emergency room visits. Treatment not only benefits patient
morbidity but can significantly reduce the economic burden of
asthma. Intervention requires effective medication plus education
of patient and physician which can increase costs. However this
investment pays good dividends by achieving good asthma control
which benefits patients, society and health care costs.
William J H Clark
Imperial College School of Medicine
National Heart & Lung Institute
London, U.K.
Early events and mediators
9:00 - 9:40 a.m.
Early intervention in atopic diseases.
Prevention and early intervention in allergic diseases of the
respiratory tract might be feasible if it is directed at the
high-risk population. At present, there are inadequate data to
predict which infants will develop atopic diseases. Environmental
manipulation, inducing breast-feeding, avoiding tobacco smoke,
major food allergens, pets and reducing exposure to domestic
mites, are reasonable recommendations. Early immunological
intervention is a possibility to influence the Th2 to Th1 switch.
Pharmacological secondary intervention is under investigation,
and results are awaited with great interest.
Charles K. Naspitz
Escola Paulista de Medecina, UNIFESP
Sao Paulo, Brazil
9:40 - 10:10 a.m.
Neuropeptides and kinins in airway allergy.
It is now well established that peptides released from neural
structures or generated from other sources may cause all the
major signs of inflammation in the airways. Recently , the
contribution of tachykinins, released from sensory nerves and
kinins, generated from plasma and/or tissue precursors have been
found to play an important role in airway allergic reaction in
experimental animals. The newly discovered, selective and potent
non peptide antagonists for bradykinin and tachykinin receptors
may unravel the role of these peptides in allergy in humans. They
may also have the potentlal as new drugs for the treatment of
allergic airway disease.
Pierangelo
Geppetti
Department of Experimental and Clinical Medicine
University of
Ferrara
Ferrara, Italy
10:10 - 10:50 a.m.
Antileukotrienes.
Studies with anti-leukotriene drugs (receptor autagonists or
leukotriene biosynthesis lnhihitors) have established that
leukotrienes mediate important components of airway obstruction
evoked by trigger factors in asthma such as allergen, exercise,
adenosine, dry cold air, platelet activating factor, and aspirin
in aspirin-intolerant asthmatics. When administered to asthmatics
with persistent baseline bronchocontriction, anti leukotrienes
cause a prompt bronchodilator response. Clinical treatment with
anti-leukotrienes has been shown to produce chronic improvement
in pulmonary function and other aspects of airway function, in
parallel with a reduction in use of bronchodilator agents. Recent
data support that inhibition of leukotrienes improve also
cellular aspects of asthmatic airway inflammation, and in
particular the infiltration of eosinophils in the airway mucosa.
During treatment with antileukotrienes there has been observed a
reduced need for rescue with glucocorticosteroids, and control of
asthma despite reduced maintenance doses of glucocorticosteroids.
The first anti-leukotriene drugs are presently being introduced
as a new therapeutic alternative in asthma. In addition, there
are observations suggesting that antileukotrienes may attenuate
certain components of allergic rhinitis, especially congested
nose and loss of smell. In conclusion, antileukotrienes comprise
a new therapeutic option which may be used for control of asthma
and prevention against airway obstruction induced by
environmental triggers.
Sven-Erik Dahln
Institute of Environmental Medicine
Karolinska Institutet
Stockholm, Sweden
10:50 - 11:10 a.m.
Coffee break
New molecular insights :
11:10 - 11:40 a.m.
Mast cell tryptase and chymase as new targets for
therapeutic intervention
Mast cell activation is a prominent feature of allergic
conditions of the respiratory tract. This cell type can release a
range of potent inflammatory mediators, but the among the most
abundant products of mast cell activation are the serine
proteases, tryptase aud chymase. Studies conducted in vitro
suggest that by acting on cellular as well as extracellular
targets, these proteases have the potential to play a key role in
processes of allergic and neurogenic inflammation, tissue
remodeling, the control of blood flow and mucus secretion. The
use of in vivo models is now providing confirmatory evidence that
tryptase and chymase may be important mediators of inflammation
and attractive targets for therapeutic intervention
Andrew F. Walls
Immunopharmacology Group
Soulhampton General Hospital
Southampton, U.K.
11:40 - 12:20 p.m.
The mode of action of steroids
Glucocorticoids are by far the most effective therapy for the
control of allergic diseases, but their molecular mechanism of
action is still uncertain. Glucocorticoids bind to a single
glucocorticoid receptor in the cytoplasm which translocates to
the nucleus where it increases the expression of certain genes
(e.g. 2-adrenoceptors). However the anti-inflammatory
effects of steroids usually involve decreased expression of
inflammatory proteins (cytokines, enzymes, adhesion molecules,
receptors) as a result of decreased gene transcription. There is
evidence that activated glucocorticoid receptors directly inhibit
activated transcription factors, such as NF-B and AP-1, that
orchestrate the expression of inflammatory and immune genes. In
addition, glucocorticoids may affect translation of some
inflammatory proteins and may increase expression of
anti-inflammatory proteins, such as interleukin-10.
Peter
J Barnes
Department of Thoracic Medicine
National Heart
& Lung Institute
London, U.K.
12 h 20 - 12 h 50
| The role of endotoxin exposure in
asthma. A dose-response relationship has been
reported between exposure to allergens and both
sensitization and occurence of symptomatic asthma while a
relation between the level of allergen exposure and the
quantified severity of chronic asthma remains
questionnable. Bacterial endotoxin has long been
recognized as a highly potent pro-inflammatory agent.
Because endotoxin is present in a variety of occupational
and general environmemts, it could be an important
contributing factor in asthma severity.
Controlled exposure to inhalation of pure endotoxin, dust
containing endotoxin and allergen extracts contaminated
by endotoxin has been evaluated in nomal and asthmatic
subjects. The prospective effect of anti-asthmatic drugs
has also been investigated. In association with allergen
exposure, the endotoxin content in house dust has been
evaluated as an important determinant in asthma severity.
Informations for the dose-response relationship to
inhaled endotoxin are available allowing to define
individual sensitivity as well as no-response threshold
of exposure.
|
Le rôle de
l’exposition aux endotoxines dans l’asthme. Une
relation dose-réponse existe entre d’une part
l’exposition à des allergènes et d’autre part
le risque de sensibilisation et d’asthme
symptomatique. Par contre, une relation entre
l’exposition allergénique et le niveau de
sévérité de l’asthme chronique n’a jamais
été démontrée. Les endotoxines bactériennes sont des
agents pro-inflammatoires puissants. Puisque les
endotoxines sont présentes dans plusieurs environnements
professionnels et généraux, elles pourraient jouer un
rôle important dans la sévérité de l’asthme.
L’exposition contrôlée par l’inhalation
d’endotoxine pure, de poussières ou d’extraits
allergéniques contaminés par des endotoxines a été
évaluée chez des sujets normaux et des asthmatiques.
L’effet protecteur de médicaments anti-asthmatiques
a aussi été investigué. En association à
l’exposition allergénique, le contenu en
endotoxines de la poussière de maison a été évalué
comme facteur important de risque d’asthme chronique
sévère. Des informations sur la relation dose-réponse
à l’inhalation d’endotoxines sont disponibles
ce qui permet de définir une sensibilité individuelle
et le seuil d’exposition n’induisant aucune
réponse.
|
Olivier
Michel (voir
aussi http://www.waste.envmed.gu.se
)
Hôpital Universitaire Saint-Pierre
Université libre de Bruxelles
Brussells, Belgium
12:50 - 02:10 p.m.
Lunch
02:10 - 02:40 p.m.
Targeting the respiratory tract with drugs.
Inhaled drug delivery assures a high concentration gradient
between the target tissue in the respiratory tract and the
systemic circulation. The ideal inhaler should provide a high and
predictable lung dose with a minimal deposition in the upper
airways. The device should be convenient with no use of additives
and should not harm the environment. The inhaler should be
age-specific to adapt to the varying compliance and ventilatory
capacity through different age groups. The clinical effect,
systemic activity, and cost-effectiveness of treatment are mainly
related to the lung bioavailability, which may differ several
fold, depending on the device chosen. In the future,
dose-recommendation should therefore relate to lung
bioavailability rather than to nominal or delivered dose.
Hans
Bisgaard
National University Hospital
Copenhagen, Denmark
Immunotherapy
02:40 - 03:10 p.m.
| Immunotherapy: state of the art. Allergen
immunotherapy was introduced to treat " pollinosis
" in 1911.
Immunotherapy using inhalant allergens to treat allergic
rhinitis an aslhma, is well proven to be scientifically
effective in selected patients with IgE-mediated disease.
It seems likely that immunotherapy acts by modifying T
cell responses either by immune deviation (increase in
Th0/Th1) or T cell anergy (decrease in Th2/Th0). The
quality of the allergen extract is critical for both
diagnosis and treatment. Indications have been recently
revised in a WHO Position Paper.
|
L’Immunothérapie
: état de l’art. L’immunothérapie
aux allergènes a été introduite en 1911 pour traiter
la " pollinose ".
L’immunothérapie avec des allergènes inhalés est
efficace dans la rhinite allergique et l’asthme
induite par les IgE. Il est probable que
l’immunothérapie agisse en modifiant les réponses
des lymphocytes T, soit en augmentant le rapport Th0/Th1
soit en induisant une anergie, ou encore en diminuant le
rapport Th2/Th0. La qualité des extraits allergéniques
est critique pour le diagnostic et le traitement. Les
indications ont été récemment revues dans un document
de l’OMS.
|
Jean
Bousquet (voir aussi http://www.montp.inserm.fr/u454/
Hôpital Arnaud de Villeneuve
Montpellier, France
03:10 - 03:40 p.m.
Peptide-Mediated regulation of allergen specific immune
responses
Allergic inflammatory responses are regulated by cytokines
derived from Th2-type helper cells. Thus, the ability to
downregulate the function of these T cells may contribute to the
improvement of clinical symptoms. Two broad approaches to CD4+ T
cell targeted immunotherapy are attracting interest, namely the
inhibition of Th2 cell activity and the induction of Thl-type
cytokines. The modulation of house dust mite specific responses
in experimental models by allergen derived peptides suggests that
T cell anergy and/or a shift in the IFN[gamma] to IL-4 ratio in
favour of the Th1 pathway are induced. These findings are
discussed in the context of clinical allergen immunotherapy.
Jonathan
Lamb
Respiratory Medicine Unit
University of Edinburgh
Edinburgh, United Kingdom
03:40 - 04:00 p.m.
Tea break
From acute to chronic disease
04:00 - 04:40 p.m.
Allergens as a Target for Treatment.
Increasing knowledge of the primary, secondary and tertiary
structure of the major indoor allergens, makes it possible to ask
specific questions about the relevance of enzymic or other
activities of these proteins to their immunogeni-city. Using site
directed mutagenesis on recombinant proteins, it is already
possible to produce molecules that have greatly diminished
reactivity with IgE antibodies. Measurement of exposure to indoor
allergens has defined dose response relationships between
exposure and disease. Thus, there are two major allergen specific
approaches to management of asthma modifying the environment and
specifically targeting different aspects of the immune response.
Thomas A.E. Platts-Mills
University of Virginia
Charlottesville, VA, USA
04:40 - 05:20 p.m.
Effects of inflammatory mediators and drugs on Mucus
Secretion and Mucociliary Function
A number of mediators and cytokines (eg. histamine, PAF,
reactive oxygen species, TNF-a) are increased in airways of
individuals suffering from allergic disorders. Utilizing guinea
pig and human airway epithelial cells in air/liquid interface
culture, which maintains their differentiated structure and
function in vitro, effects of these substances on secretion of
mucin were studied. Histamine, PAF, exogenously-generated
oxidants, and TNFa all increased secretion of mucin, and appeared
to do so via a convergent intracellular pathway involving nitric
oxide (NO) as a critical signaling molecule. Since NO can also
modulate ciliary beat frequency, it may be an important molecule
regulating mucociliary clearance under normal and pathologic
conditions. The mode of action of drugs which interfere with
mucus production and which may have clinical relevance will be
reviewed.
Kenneth B. Adler
Professor of Cell Biology
Department of Anatomy, Physiological Sciences and Radiology
College of Veterinary Medicine
North Carolina State University
Raleigh, NC, USA.
05:20 - 06:00 p.m.
Remodeling of Lung Tissue Consequent to Chronic Injury.
Lung injury is induced by a number of environmental agents
including toxic particles and gases, allergens and infectious
organisms. If exposure takes place chronically, the conducting
airways and gas exchanging regions of the lung are remodeled by
the elaboration of extracellular matrix. This results in scarring
that contributes to the thickened, hyperreactive airways of
chronic asthma and the severe dyspnoea of hypersensitivity
pneumonitis and the pneumoconioses. Transgenic and molecular
biology techniques allow a focus on factors such as
platelet-derived growth factor, the transforming growth factors,
and TNF-a as potential mediators of lung remodeling and as
targets for therapeutic intervention.
Arnold
R. Brody
Department of Pathology
Tulane University Medical School
New Orleans, LA, U.S.A.
Saturday April 4, 1998 SATELLITE Chaired by:
G. PELTRE (F)
Progress in molecular diagnostics of allergy
8:30 - 9:00
Registration of the participants of the satellite
9:00 - 9:35 a.m.
Introduction: From past to future.
Ever since the discovery of human IgE it has been possible to
perform allergy diagnosis at the molecular level. Quantitative
immunoelectrophoretic methods could measure patients individual
responses towards single allergen molecules. Progress in
separation abilities combined with genetically engineering have
further revealed individual responses towards isoforms of
allergens. Very recently 3-D structure of allergen molecules
indirectly elucidate potential allergenic epitopes. Current
activities within genetics of allergy (in particular HLA and
allergy) may create a basis for molecular diagnostics of allergy
at the gene level.
Henning Lowenstein
Alk-Abello Research
Horsholm, Denmark
9:35 - 10:10 a.m.
Environmental Aspects of Allergy Diagnostics.
Sensitization to one or more of the major perennial allergens
is a major risk factor for asthma. Specific diagnosis is
essential for understanding the epidemic of asthma evaluating
individual cases and monitoring treatment. Sensitization is
currently assessed by skin tests or in vitro assays for IgE. It
is also possible to quantitate IgG and T cell responses, however
the clinical significance of these measurements is not yet clear.
In all cases it is essential to understand the patients exposure
which is best achieved by assay of specific allergens in the
environment. Monoclonal antibody based assays for the indoor
allergens have also allowed development of precise avoidance
measures for the major indoor allergens.
Thomas A.E. Platts-Mills
University of Virginia
Charlottesville, VA, USA
10:10 - 10:45 a.m.
Recombinant allergens: diagnosis and therapy of the future.
Molecular biology (and in particular cDNA cloning) provided
us with an increasing number of well characterized recombinant
allergens in recent years. As these molecules can - in comparison
to natural allergens and allergen extracts - easily be
standardized and produced in large amounts, they represent
candidates for diagnosis and specific therapy of Type-l allergy
in the future. The production of particular variants of
recombinant allergens (isoforms, mutants) could further increase
their potential in this respect: molecules for a sensitive
diagnosis should possess high IgE-binding capacity, allergens for
therapeutical use should target specific lymphocytes and at the
same time display reduced allergenicity. Pollen allergens with
these properties have been produced and will be presented.
Christof
Ebner
Institute of general and experimental pathology
Vienna, Austria
10:45 - 11:15 a.m.
Coffee break
11:15 - 11:50 a.m.
| Diagnostics in food allergy. Food
allergy is a public health problem because it can be
fatal, but also because its chronic nature impairs
quality of life or generates costs. The diagnosis of food
allergy requires demonstration of sensitization (assays
of specific IgE and skin tests). Reactivity is confirmed
by double-blind oral challenge, determination of
intestinal permeability or motility, or even by cytokine
release.
|
Diagnostics dans
l’allergie alimentaire. L’allergie
alimentaire est un problème de santé publique parce
qu’elle peut être responsable de décès, mais
aussi parce que sa chronicité altère la qualité de vie
ou génère des coûts. Le diagnostic impose la mise en
évidence d’une sensibilisation (dosage d’IgE
spécifiques et tests cutanés). La preuve de la
réactivité est fournie par les provocations orales en
double insu, la mesure de la perméabilité ou de la
motricité intestinales, voire par la libération des
cytokines.
|
Claude André
Stallergnes S.A.
Antony - France
11:50 - 12:25 p.m.
IgG4 antibody assays in allergy diagnostics.
IgG4 antibodies have been known to be associated with IgE
mediated responses (both allergic and helminth-associated)
because both depend on TH2 cytokines. Debates have been going on
for 20 years on both extremes of potential relevance: a possible
pathogenic role for allergen-specific IgG4 on the one hand and a
protective (allergen-blocking) role on the other. A further
complication has been added by the observation that IgG4 is a
natural bispecific antibody, i.e. it has two different
antigen-binding sites.
Rob Aalberse
Department of Allergy
Central Laboratory of The Netherlands Red Cross Blood Transfusion
Amsterdam, The Netherlands.
12:35 - 01:00 p.m.
| Non-IgE antibodies to allergens: their
relevance in diagnostics A simplified definition of
allergens could be that they are antigens recognized by
IgE antibodies. Allergic patients sensitized to a given
allergenic source, such as mites or pollen, produce
specific IgE to allergens but also non-IgE antibodies to
either allergens or other antigens present in the
allergenic source. These later antibodies are usually far
more numerous and, so, should be easier to detect than
the allergen specific IgE. Their immunoglobulin nature is
also important. Many questions will be raised. Are these
non-IgE antibodies involved in the allergen presentation
or clearance in vivo ? Are they competing with IgE for
their binding with allergens ? Do they interfere with IgE
in vitro diagnostics ? Do they have predictive values for
the induction or the evolution of the disease ? What is a
" normal " immune response, from non allergic
individuals, to allergenic extracts ?
|
Les anticorps
non-IgE anti-allergènes : leur importance en diagnostic. Une
définition simplifiée des allergènes est qu’ils
sont des antigènes reconnus par des anticorps de classe
IgE. Les malades allergiques sensibilisés à une source
d’allergène, telle que les acariens ou les pollens,
produisent des IgE spécifiques des allergènes mais
aussi des anticorps non-IgE dirigés soit contre les
allergènes ou d’autres antigènes présents dans la
source d’allergènes. Ces derniers anticorps sont
habituellement beaucoup plus nombreux et donc devraient
être plus facilement détectables que les IgE. Leur
nature immunoglobulinique est aussi importante. De
nombreuses questions se posent alors. Ces anticorps
non-IgE sont-il impliqués dans la présentation des
allergènes ou dans leur élimination in vivo ?
Entrent-ils en compétition avec les IgE dans leur
liaison avec les allergènes ? Interfèrent-ils avec des
IgE dans le dosage de ces derniers in vitro ? Peuvent-ils
prédire l’induction ou l’évolution de la
maladie ? Quelle est la réponse immunitaire
" normale " d’un individu non
allergique aux extraits d’allergènes ?
|
Gabriel Peltre
Immuno-Allergie, Institut Pasteur
Paris, France.
Institut
Pasteur, Paris, France.
Contact : Ludovic Drye, Institut Pasteur,
C.I.S., 28 rue du Docteur Roux, 75724 Paris Cedex 15 France
Fax 33 1 40 61 34 05 - E.mail : l drye
http://www.pasteur.fr/Conf/euroconf.html
. 
Asmanet
Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 28 Octobre 1997-Dernière mise à jour: 21/07/98
Le secret des
correspondances transmises sur le réseau Internet n'est pas
garanti.
Toute personne citée dispose d'un droit d'accès, de
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