Transcript Immunotherapy: Radical treatment of Allergic diseases

Immunotherapy: Evidence in
atopy
Carla Irani, M.D
Allergy/Clinical Immunology
Epidemiology
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Epidemiologic studies of temporal and
geographic variation in asthma morbidity have
identified asthma as an important public health
concern.
There is tremendous increase in the incidence
of asthma and allergic rhinitis
Most recently, the NIH joined forces with the
World Health Organization to find ways to lessen
the global impact of asthma. (GARD)
Allergic Rhinitis and Comorbid
Airway Diseases
Spector SL. J Allergy Clin Immunol. 1997;99:S773-S780
(J Allergy Clin Immunol 1999;104:S1-9.)
Trends in estimated average annual rate of self-reported asthma during preceding 12 months by age group, United States, 1980 to 1993 and 1994.
Epidemiologic Links between Allergic
Rhinitis and Asthma
Allergic Rhinitis and Asthma Have Similar Prevalence Patterns
Allergic Rhinitis
Asthma
UK
Australia
Canada
Brazil
USA
South Africa
Germany
France
Argentina
Algeria
China
Russia
UK
Australia
Canada
Brazil
USA
South Africa
Germany
France
Argentina
Algeria
China
Russia
0
5
10 15 20 25 30 35 40
% prevalence
0
5
10 15 20 25 30 35 40
% prevalence
Study of worldwide prevalence of atopic diseases in 463,801 children 13–14 years of age. Children self-reported symptoms
over 12 months using questionnaires.
Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet 1998;351:1225–1232.
General Principles of
Allergy Management
History of Allergen Immunotherapy
History of Allergen Immunotherapy
The Science of Allergen
Immunotherapy
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To paraphrase William Osler, the father of
American medicine:
The practice of allergen immunotherapy is an
art based on science.
Thirty years ago there was little science and
today there is considerable science as to how
allergen immunotherapy should be prescribed
and administered
Most common allergens in
Lebanon
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Dust mites: farinae and pteronyssinus
Grass: Phleum ,Dactylis and Lolium
Olive (cross-reactive with ash)
Pine, not very allergenic
Parietaria
Molds: Aspergillus and Altenaria
Weeds: Ambrosia
Coackroaches: Blatella germanica
Allergen Immunotherapy
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Introduced by Leonard Noon in 1911, then
Freeman
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Historically: Weekly injections given before
the season
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1920: Perennial treatment
Indications
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Presence of a demonstrated IgE-mediated
disease (ST, RAST)
Documentation that specific sensitivity is
involved in symptoms
Severity, duration of symptoms and incomplete
response to pharmacotherapy
Venom immunotherapy: Hx of severe systemic
allergic reaction
Contra-indications
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Inability of patients to comply
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Auto-Immune diseases & immune deficiencies
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Age: Chidren < 5 years
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Uncontrolled severe asthma (FEV1 < 70 % predictive
value)
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Presence of other immunologic diseases
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Treatment with b-blockers
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Malignancy
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Chronic mouth lesions (sublingual immunotherapy)
Immunotherapy and pregnancy
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Risk for a systemic reaction leading to
abortion: one case report
No increase in prematurity, toxemia,
abortion, neonatal death or congenital
malformations
Fewer immediate skin tests in children
whose mothers received IT while in utero
(significant for grass pollen)
Dosage schedules
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There is a dose-response relationship
Historically: coseasonal and preseasonal, not
recommended
Injections are started at 1:10,000W/V, or
1:100,000 for more sensitive patients
Injections are given weekly until patient reaches
the maintenance dose of 0.6 to 0.8ml of 1:100,
then interval of 4 to 6 weeks for 3 years
Sublingual immunotherapy is administered
following a protocol for 3 years
Dosage schedule
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Reduce volume administered (eg: 0.5 to
0.35) when a new vial of extract is given
Identify carefully at each time: patient’s
dose schedule and patient’s vial
Observe for 20-30 min after injections for
evidence of reactions in the case of
subcutaneous immunotherapy
Sublingual immunotherapy is administered
at home
Mechanisms
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Complex, depends on the allergen and
route of immunization
Diminution of TH2 response and
enhancement of TH1
Decreased specific proliferation response
to allergen
Increase of CD8+ lymphocytes
Mechanisms
Effect on specific IgE:
 Early rise in specific IgE
 Suppression of seasonal rise of specific IgE
 Later lowers specific IgE levels
 Decreased expression on FceRII on B cells
 Effect an specific IgG:
 Initial rise in specific IgG1 and IgG4
 Specific IgG1 predominates early, IgG4 by
end of year 2
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Mechanisms
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Nonspecific loss of basophil histamine
release following allergen challenge
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Decreased cytokine release: IL4, PAF,
HRF, TNF, MIF
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Increased production of IFN-g, increased
mRNA for IL-2 with a good correlation
clinically
J Allergy Clin Immunol 97:1356-1365.1996
JACI 2005
WHO position paper:Allergen immunotherapy
Bousquet J, Lockey RF, Malling HJ et al.
Allergy 1998;53:suppl 44:1-42
Effective in IgE-mediated disease with a
limited spectrum (1 or 2) of allergies
 Effective in allergic rhinitis/conjunctivitis
allergic asthma and systemic reactions to
wasp/bee venom
 Should be combined with allergen
avoidance, pharmacotherapy and patient
education
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Grass pollen immunotherapy for
hayfever
Varney va et al BMJ 1991;302:265-9
Immunotherapy for rhinitis (43 studies)
Malling HJ. Allergy 1998;53:461-472
Grass pollen immunotherapy for seasonal
rhinitis/asthma
Walker SM et al., J Allergy Clin immunol 2001;107:87-93
Randomized placebo controlled studies with SLIT
Preventive Effects of immunotherapy:
Novel sensitization
Immunotherapy and Asthma
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N Engl J Med 1997;336:324-31 Adkinson et al:
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No benefit in children sensitized to many
allergens, but decrease in use of inhaled
steroids
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N Engl J Med 1999;341:468-475 Durham et al:
Immunotherapy for grass-pollen allergy for 3
to 4 years induces prolonged clinical
remission accompanied by a persistent
alteration in immunologic reactivity
Immunotherapy and Asthma
Cochrane collaboration:
 Fifty-four randomized controlled trials were
analyzed:
 25 for house mite allergy
 13 pollen
 8 animal dander
 2 Cladosporium
 6 with multiple allergens
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Immunotherapy and Asthma
Allergy 1999 Abramson et al: The
Cochrane collaboration:
 Immunotherapy may reduce asthma
symptoms and use of medications
 But the size of the benefit compared to
other therapies is not known
 The possibility of adverse effects
(anaphylaxis) must be considered
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Immunotherapy and Asthma
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NHLBI recommendations:
If avoidance is not possible
Appropriate treatment fails to control
allergic asthma
Greater efficacy in children and young
adults
Greater likelihood of success if single
sensitivity
FEV1 at least 70% of predicted
The Origins and Prevention of Atopy and Asthma .
Immunotherapy as a preventative asthma therapy: The
PAT trial
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In a large multicenter trial 205 children
aged 6 to 14 years with grass and/or
birch pollen allergy but without any other
allergy, were randomized either to
receive specific immunotherapy for 3
years or to an open controlled group
Möller et al, Pollen immunotherapy reduces the development of asthma
in children with seasonal rhinoconjunctivitis 8the PAT-Study. J Allergy
Clin Immunol 2002; 109:251-6
PAT Trial
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Subjects had moderate to severe hay fever symptoms
At inclusion none reported asthma with need of daily
treatment.
Symptomatic treatment was limited to loratadine,
levocabastine, sodium cromoglycate, and nasal
budesonide.
Asthma was evaluated clinically and by peak flow.
Methacholine bronchial provocation tests were carried
out during the season(s) and during the winter.
Before the start of immunotherapy, 20% of the children
had mild asthma symptoms during the pollen
season(s).
Allergen immunotherapy : the future
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Conventional subcutaneous
immunotherapy
Alternative routes: mainly sublingual
Recombinant allergens
Modified allergens
Peptides
DNA vaccines
Adjuvants (ISS, IL-12, mycobacteria)
Anti-IgE
Immunotherapy for the 21st
century
T cell strategies of allergy vaccination
Overlapping peptides of Fel d 1 : Allervax
Cat
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Genetic immunization
CpG motifs or immunostimulatory sequence
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T cell strategies
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B Kay (AAAAI 2001):multiple, short,
overlapping peptides containing T cell
epitopes can induce both peptide and whole
allergen-specific hyporesponsiveness
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Norman et al Am J Resp Crit Care Med 1996
Allervax: 2 reactive peptide for chain 1, safe
and efficacious
 Pene et al JACI 1997 Significant decrease in IL4
secretion after 6 wks of high dose Allervax
Cat
DNA-based immunotherapeutics
of allergic disease
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Immunization with plasmid gene vaccines:
Induction of Th1-biased immune response
and prevention of development of Th2
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Allergen mixed with immunostimulatory
aligodeoxynucleotide (ISS-ODN or CpG
motifs): Cryptic immunostimulatory DNA
sequences which provide Th1 adjuvant
activity for the immune responses
DNA-based immunotherapeutics
of allergic disease
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Physical allergen-ISS-ODN conjugates (AIC):
More immunogenic than native antigens and
antigens/ISS-ODN cocktails, and more
effective in the prevention of allergic
hypersensitivity responses
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Immunomodulation with ISS-ODN alone:
Effective allergen-independent
immunomodulator, in early and late
phase(short lived, proven in mice only)
Specific immunotherapy in
perennial rhinitis
Mild rhinitis
Moderate rhinitis+/conjunctivitis
Severe rhinitis+/conjunctivitis
Allergen avoidance (when possible)
Pharmacotherapy
Consider immunotherapy
WHO Position Paper 1997
Specific Immunotherapy and
Asthma
Intermittent asthma Mild persistent Moderate Severe
Persistent persistent
asthma
asthma
asthma
Pharmacotherapy
Consider
immunotherapy
WHO Position Paper 1997
Immunotherapy in Atopic
Dermatitis (AD)
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No evidence in large studies
May be useful when done for allergic
rhinitis in a patient suffering as well from
atopic dermatitis
Atopic dermatitis is an atopic state not
always caused by allergens
But!! Dust mites have been shown to
exacerbate AD
Toward Allergy and Asthma
Prevention
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There is justifiable hope that some
chronic and debilitating diseases,
such as asthma and allergic rhinitis,
that markedly affect the lives of the
young and the old equally can be
prevented before they start or can be
stopped before resulting in
irreversible harm.