Académique Documents
Professionnel Documents
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Rebecca Dearman
School of Biological Sciences
Faculty of Biology, Medicine and Health
University of Manchester
OVERVIEW
ORCHESTRATION OF IMMUNE RESPONSES
Immune system must counter range of threats
Viruses
Bacteria
Fungi
Parasites
SHAPING IMMUNE RESPONSES FOR SPECIFIC THREATS
CARDINAL CHARACTERISTICS
OF ADAPTIVE IMMUNE RESPONSES
memory
specificity
discrimination between self and non-self
INDUCTION/SENSITISATION
first exposure, individual is primed
ELICITATION
subsequent exposure to same allergen,
sensitised individual shows clinical manifestations
ALLERGIC REACTIONS:TYPE II
specific immune responses to innocuous antigens
resulting in pathology (type II hypersensitivity)
penicillin
ALLERGIC REACTIONS:TYPE II
specific immune responses to innocuous antigens
resulting in pathology (type II hypersensitivity)
penicillin
eg serum sickness
(use of therapeutic anti-venom Ig etc)
(more common in autoimmune disease)
eg systemic lupus erythematosus
ALLERGIC REACTIONS:TYPE III
Antigen/antibody
complexes
antibody against
foreign serum
Plasma level
foreign proteins
serum
proteins
Apr 2014
Father, 38, builder,
Apprentice dies from 18,severe
with nut allergic
allergy who
reaction from
collapsed and died curryan containing
hour after eating a Korma
peanuts
Police investigating the death of a father who had a severe allergic
curry wasn't carrying his EpiPen because he
reaction to nuts have arrested two men believed to work at the
wanted
takeaway whichtoserved
keep him athe outline
meal containing of his skinny jeans
peanuts.
Paul Wilson, 38, died after eating a curry from a takeaway which is
believed to have contained peanuts.
SHAPING IMMUNE RESPONSES FOR SPECIFIC THREATS
Th2 cells
from circulation
ACUTE RESPONSE CHRONIC RESPONSE
mast cell degranulation Release of cytokines (Th2 cells)
airway obstruction eosinophil granule proteins
leaky blood vessels = chronic inflammation
Th2 CYTOKINES IN TYPE I REACTIONS
intestinal
smooth
muscle
systemic histamine
release
vomiting anaphylaxis
anaphylaxis
diarrhoea
DIAGNOSIS
DETECTION OF IgE
Specific serum IgE ex vivo (RAST/IMMUNOCAP etc)
Skin prick tests/prick to prick tests
PROVOCATION CHALLENGE
Food allergy : DBPCFC (double blind placebo controlled food challenge)
Rhinitis : nasal challenge
Asthma : bronchial provocation test
AVOIDANCE
At 60 months :
Induces altered immune response (IgG4IgE)
Prevention and cure
Low incidence of adverse effects
Follow up : no difference in energy consumption
Du Toit et al, 2015. Randomized trial of peanut consumption in infants at risk for peanut allergy.
N Engl J Med. 372:803-13.
TREATMENT : IMMUNOTHERAPY
PREVENTION LEAP follow up study (LEAP-On)
Avoiders
Consumers
Du Toit et al, 2016. Effect of avoidance on peanut allergy after early peanut consumption.
N Engl J Med. 374:1435-43.
TREATMENT : IMMUNOTHERAPY
MONOCLONAL ANTIBODY THERAPY (Omalizumab)
Humanised monoclonal antibody
Approved in US in 2003 for moderate/
severe uncontrolled allergic asthma
Also for chronic urticaria (Phase I/II/III/IV)
Omalizumab
Binds circulating IgE
IgER expression
mast cell degranulation IgE
Expensive
Subcutaneous administration
Food allergy and rhinitis trials :
An adjunct to SIT?
Tan et al, 2016. Novel biologicals for the treatment of allergic diseases and as
Curr Allergy Asthma Rep. 16:70 (Epublication)
TREATMENT : NEW BIOLOGICS
Treatment Drug/agent Company Mechanism Development
Reduces free Phase I/II studies
QGE031 plasma IgE levels, Asthma, urticaria
Anti-IgE mAb Novartis
(ligelizumab) prevents IgE binding
to FcRI/II
Binds to IgE- Phase II study
expressing B cells Asthma, urticaria
Quilizumab Anti-M1 Genentech
and induces
apoptosis
Blocks CD23, Phase I study
reducing IgE
Lumiliximab Anti-CD23 Biogen
production and
transport
Phase III study
Mepolizumab
AntiIL-5 mAb GlaxoSmithKline Blocks IL-5 Approved for severe
(Bosatria)
eosinophilic asthma
Blocks IL-5 binding Phase II/III studies
Benralizumab AntiIL-5R MedImmune
to IL-5R Asthma, COPD
Phase II/III studies
Regeneron Blocks IL-4 and IL-13
Dupilumab AntiIL-4R mAb Asthma, atopic
Pharmaceuticals binding to IL-4R
dermatitis
Phase II/III studies
Lebrikizumab AntiIL-13 Genentech Blocks IL-13
Asthma
Blocks TSLP binding Phase I/II studies
AMG 157 Anti-TSLP Amgen
to receptor Asthma
Stimulates TLR9 and
AIC (CpG conjugated TLR9 agonist NIH Immune Phase II study
TH1 responses
to Amb a 1) (adjuvant) Tolerance Network Allergic rhinitis
during ragweed IT
Bauer et al, 2015. The future of biologics: applications for food allergy. J Allergy Clin Immunol.
ALLERGIC REACTIONS: TYPE IV
methylisothiazolinone (MI)
Allergen of the year 2013
T clonal expansion of
T
T T allergen-specific T
T T lymphocytes
T
arrival of skin-homing
allergen-responsive
T lymphocytes ELICITATION
T T immune PHASE
T T activation
cutaneous inflammation
ALLERGIC REACTIONS:TYPE IV
TREATMENT :
Articles
Anagnostou et al, 2014. Assessing the efficacy of oral immunotherapy for the
desensitisation of peanut allergy in children (STOP II). Lancet 383:1297-1304.
Bauer et al, 2015. The future of biologics: applications for food allergy. J Allergy Clin
Immunol 135: 312-23.
Du Toit et al, 2015. Randomized trial of peanut consumption in infants at risk for peanut
allergy. N Engl J Med 372: 803-13.
Du Toit et al, 2016. Effect of avoidance on peanut allergy after early peanut consumption.
N Engl J Med 374:1435-43.
Johnston et al, 2014. The immunology of food allergy. J Immunol192:2529-34.
Martin SF, 2015. New concepts in cutaneous allergy. Contact Dermatitis 72:2-10.
McFadden et al, 2013. Why does allergic contact dermatitis exist? Br J Dermatol168:692-9.
Tan et al, 2016. Novel biologicals for the treatment of allergic diseases and asthma.
Curr Allergy Asthma Rep 16:70 (Epublication)
Wood, 2016. Food allergen immunotherapy: Current status and prospects for the future.
J Allergy Clin Immunol 137:973-82.