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How can allergy develop?

Interaction of genes and environment


How many children have allergic diseases?

up to 40%
particularly in western populations


What is the spectrum of allergic diseases?

- atopic dermatitis (eczema)
- asthma
- food allergy
- allergic rhinitis


Is there a rising prevalence of immune disorders?

- immune mediated diseases such as allergy and autoimmunity are rising at alarming rates
- particularly in developed countries
- dramatic increases e.g. MS, Crohn's, asthma, type 1 diabetes
- true for many other allergic type disease
- also increased icidence of food allergy

e.g. ACT: exponential rise in incidence
- peanut sensitisation and allergy


What is sensitisation?

the atopic status of an individual
characterised by IgE when you do a skin prick test
positive skin prick test
- introduce allergen onto the skin and develop a wheel and flare
- characteristic of an IgE response to that protein


What is anaphylaxis? How have rates of anaphylaxis changed ?

most severe form of allergy

250% increase in total anaphylaxis
- 230% increase in non-food anaphylaxis
- 350% increase in food anaphylaxis


What is the population at greatest risk of anaphylaxis? Why?

- 0-4 yo
- infants and children
- early life period is important in development of the immune system
- environment factors during that period will influence whether you develop an immune response (in combination with some genetic susceptibility)


What foods have contributed to this exponential rise of food anaphylaxis?

- peanuts (328% increase)
- treenuts and seeds
- fish
- crustaceans
- eggs
- milk products (154%)

- fruits, vegetables
- food additives


What are determinants of allergic disease?

- genes + early life environment
-- e.g. vitamin D, UV light, Diet, microbial exposure
-- neonatal period
-- prenatal period

- epigenetic modification
- gene expression
- altered immune tolerance
- disease


What is perhaps the most important single risk factor for the development of allergy?

microbial exposure

reduced exposure to pathogens will increase the risk of developing allergies in later life
(hygiene hypothesis)


What do we see in mice bred in germ free conditions?

- small underdeveloped Peyer's Patches that lack germinal centres
- few IgA plasma cells and CD4+ T cells in the lamina propria of intestinal wall
- reduced number of intraepithelial lymphocytes (IEL)

- fail to develop oral tolerance
- have persistent Th2 dependent responses


Can abnormalities seen in mice bred in a germ free environment be corrected?

- yes, these abnormalities can be corrected by reconstitution of intestinal microbiota but ONLY if reconstitution of microbiota occurs in neonatal period
- a lot of strategies around reversing dysbiota


What would a normal immune response be, simplistically?

Th1 Th2 balance with Th1 healthy response
lack of reg function can lead to Th2 skewed response


What is altered in allergic children?

- intestinal microbiota
- lower levels of probiotic bacteria (e.g. lactobacillus and bifidobacteria)
- higher levels of pathogenic bacteria (e.g. Staphylococcus aureus and Clostridium difficile)


What do we see in the composition of Bidifobacterium flor a in children with allergic disease?

- different
- adult-like Bifidobacterium flora with a predominance of B adolescentis, whereas healthy infants have a predominance of B bifidum
- reduced adhesion to human intestinal mucus
- induce less IL-10 production in vitro (IL-10 are important for maintenance of oral tolerance)


When do these changes occur?

- precede the development of allergic disease


What do we see in children who develop allergic disease?

- lower counts bifidobacteria at 1 mos and bacteroides at 12 mos
- less often colonised with enterococci at 1 mos and bidifobacteria at 1 year
- higher counts of clostridia in first weeks and at 3 months
- more often colonised with staphylococcus at 6 mos


What are the earliest times at which you can detect a clinical allergy in a child?

3 - 6 months


What plays a critical role in the maturation of the immune system?

- healthy intestinal microflora plays a critical role in the maturation of the immune system and development of tolerance required to avert allergic response


What are strategies to promote a healthy microbial flora?

- may offer novel approaches to prevention or treatment
- probiotics
- diet


What is the incidence of food allergy?

- overall ~2-5% of population experience food allergy reactions
- more common in children
-- 5-10% children experience food allergic reactions
-- 30 - 40% being sensitised
-- 2% adults experience food allergic reactions
- most food allergies resolve with increasing age


What 8 major food groups cause __% of food allergy?

>90% of food is caused by
- cow's milk
- hen's egg
- peanut
- tree nuts
- fish
- wheat
- shellfish
- soya bean


Which are the food allergens that tend to stay with you?

- peanut, fish and shellfish (only about 20% resolution by 5yo cf 80% of other food allergens)


What are common food allergens in children and adults?

- egg, milk, peanut
- soy, wheat, fish

- peanut, tree nuts, fish, shellfish
- more serious in nature


What do we talk about when talking about allergy?

predominantly IgE mediated


What kinds (?) of allergy are there?

- IgE mediated
- Non IgE mediated (unknown aetiology type basis, distinct mechanism)
- mixed


When does onset of IgE mediated allergy occur?

< 30 minutes - 1 hour
generally occur very quickly


What does an allergic reaction involve? (re systems)

systemic reactions

- erythema
- urticaria
- angiodema
- eczema
- vomiting
- diarrhoea
- cramps
- cough
- sneezing
- stridor wheeze
- hoarse voice
- hypotension


What is urticaria?

- characteristic rash that can occur all over the body
- hours to days


What is angioedema?

- dilatation of capillaries around eyes and lips


If angioedema occurs very quickly what would this indicate?

food allergy


What signs of airway involvement are indicative of an allergic reaction?

- hoarse voice
- difficulty swallowing
- feeling of tightness in the throat
- persistent coughing
- noisy breathing - stridor and/or wheeze
- difficulty breathing


What are the signs of an allergic reaction mediated by the cardiovascular system?

- drowsy
- collapse
- pale and floppy (infant or young child)


What do we know about strategies to manage, treat and cure food allergies?

- allergen avoidance
- education
-- recognition and management of allergic reactions and anaphylaxis
-- action plan

- adrenaline autoinjector


Do we have treatment/cure for food allergy?

no cure
- limited treatment except for adrenalin shot


What is the principle reason that management of food allergies is pretty limited?

allergen avoidance is difficult to achieve
- 50% of children have an accidental ingestion within 1 year
- in fatal cases, most were aware of their allergy but failed to avoid the food
- in 40-100% of fatal reactions, the food was prepared outside the home (key point)

provision of an EpiPen has a limited impact
- 45% carried it, 10% expired, only 32% could use it correctly
- use is not intuitive and requires regular training
- in fatal cases, 12-14% received early, repeated doses of adrenaline


What are mucosal immune responses?

key effector cells and molecules:
- IgA
- Tregs --> IL-10, TGF-beta
- IELs

key types of cells and molecules that drive oral tolerance
measure these molecules to understand development of allergy or impact of certain therapeutic mechanism


How is food allergy considered a loss of tolerance?

- food allergy is associated with increased Th2 and reduced Th1 activity as compared to healthy non-allergic subjects
-- cow's milk allergy
-- peanut allergy

- resolution of food allergy is associated with normalisation of allergen specific T helper responses
-- Th1 predominant responses similar to that observed in non-allergic subjects
-- decreased IgE binding to allergenic epitopes
e.g. due to reduction in affinities or increased IgG4s (blocking antibody, compete with IgE for the antigen)

reduced T regulatory cell numbers and activity
- fewer TGFb+ lymphocytes in duodenal epithelium and lamina propria in subjects with food allergy
- reduced TGFb expression by epithelium and milk-specific lymphocytes

resolution of food allergy is associated with increased allergen-specific T-reg
- increased IgG4 binding to allergenic epitopes


What does an immune response look like in food allergy?

- dendritic cell is the driving cell behind immune responses
- if an allergen comes into contact with a DC via a specific receptor generally you get a Th1 or a Th2 skewing
- in allergy this is Th2 biased
- produces allergy through release of key cytokines such as IL-4, IL-13, IL-5
- IgE production
- at the same a Th2 based response inhibits a Th1 response
- defect in Treg response probably due to loss of tolerance


What are two aims important to the development of food allergy clinical trials?

- the ability to tolerate a food while ingesting regular doses of that food
- rapidly reversible
- mediated by changes in effector cells (mast cells, basophils)
- only really occurring while you are under that programme

Tolerance (gold standard)
- ability to tolerate a food after a period of time has elapsed since ingesting the food
- believed to reflect an immunologic response involving regulatory T cells or other T-cell subsets and/or allergen-specific anergy and clonal deletion
- expected to persist for at least months or years after the food therapy has been discontinued


How do we measure desensitisation and tolerance?

- desensitisation is measured by performing oral food challenge while a subject is still receiving treatment
- e.g. still on immunotherapy, eating regular doses of a food

- tolerance is tested by performing oral food challenge after discontinuing food ingestion for a period of time
e.g. at least 2 - 4 weeks after treatment is stopped


What are immunological effects of immunotherapy?

- therapies that will reshape the immune system
- induction of specific Tregs
- suppressive cytokines
- reduced Th2 responses
- reduced cytokines such as IL-4
- perhaps increased Th1

- reduced IgE, increased IgG4, IgA - biomarkers measured that correlate with resolution of allergen


What were the early forms of immunotherapy for food allergy?

Subcutaneous immunotherapy for peanut allergy
- desensitisation (increased threshold dose from 178mg to 2805mg (20x)) in those that could continue maintenance
- high rate (39%) serious systemic reactions during maintenance
- subcutaneous immunotherapy stopped for food allergies due mostly to this


What is oral immunotherapy for food allergy?

case reports of desensitisation following OIT
- 12yo girl desensitised and remained on cow's milk
- 6 yo girl desensitised after 4 mos of cow's milk OIT
-- decreased milk IgE, increased milk IgG4, IgA
-- increased IFNg and decreased IL-4 production

pilot studies, case series and RCT of OIT
- effective for induction of desensitisation
- few have assessed for tolerance...

very difficult to judge the efficacy of these therapies because of the different ways they have been conducted


How do we know that OIT works for desensitisation?

RCT of CM, egg and peanut OIT
- consistently report complete desensitisation (pass food challenge while on OIT) in 33% to 90% of subjects

cochrane meta-analysis of CM OIT confirmed beneficial effect of OIT to induce desensitisation vs elimination diet
- NB: terminology "total tolerance" to denote desensitisation
- 4 RCT included
- all assessed for desensitisation (not tolerance)


Can OIT induce tolerance?

- key biomarkers seen in all
- small studies
- mostly not controlled
- one had randomised control trial
- OIT vs avoid
- programme had no effect on tolerance compared to avoidance

High dose egg OIT
- tolerance induction
- 15 subjects as placebo
- 40 subjects in treatment
- followed up to at least 2 yo
- in treatment group up to 30% achieved tolerance
- 0% achieved tolerance in placebo
- significant advance in terms of what we know about OIT for tolerance (at least in egg)


So what is OIT able to induce?

can induce desensitisation in majority of patients
- allergic reactions during treatment are common
- severe reactions are uncommon (10-20%)
- immune effects observed in most studies
- can be applied in children with severe allergy

BUT limited ability to induce tolerance


What are the existing protocols for OIT for food therapy?

- low doses of allergen: <1 year


What was seen in long term follow up of OIT?

Milk OIT for up to 4.5 years
- well tolerated
- regular open ingestion of milk
- recurrence of allergy in subjects who discontinued OIT for periods of a few weeks
- no evidence of tolerance despite prolonged OIT


How could the effectiveness of OIT be enhanced?

- higher maintenance dose?
- inclusion of an adjuvant?


What are adjuvants in immunotherapy?

a new class of adjuvants - immune response modifiers
- proposed as a strategy for modulating immune responses
- targeting of TLRs with TLR ligands linked to allergens
- aim is to restore the Th1/Th2 balance

CpG-containing-DNA-allergen complexes
- marked increase in allergen specific Th1-cell responses
- effective in clinical trial for ragweed allergic rhinitis
- TLR9 ligand

monophosphoryl lipid A, a bacterial cell-wall component that binds TLR4
- improved symptom and medication scores in clinical trial
- reduced seasonal increase IgE, increase IgG1/IgG4

adjuvants = MAMPS
- linked to an allergen
- signal through the dendritic cell to promote Th1 or Treg responses that inhibit Th2 response


What is PPOIT?

- probiotic (LGG - one of the most well recognised probiotics) and Peanut OIT study
- study just completed
- children with clinically confirmed peanut allergy
- randomised
- received probiotic and peanut OIT (adjuvant), oher placebo
- 70 children in trial

- blood, stool, saliva samples taken at various time points
- quality of life, SPT
- given peanut challenges at end of trial - desensitisation and tolerance
- assessed all other factors

- preliminary data encouraging
- most that generated tolerance were in treatment group


How many people are affected by food allergy?

- food allergy affects up to 10% of children and 2% of adults, and burden is rising exponentially


What are current major issues re: allergy?

- currently no effective treatment
- avoidance is difficult to achieve
- substantial impact on quality of life


What treatments have been trialled?

- Oral immunotherapy offers potential approach for tolerance
- use of immune modifying adjuvants in conjunction with OIT
- other non-allergen specific approaches e.g. FAHF