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lecture 22 Flashcards

Food Allergy Future therapies

1
Q

How can allergy develop?

A

Interaction of genes and environment

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2
Q

How many children have allergic diseases?

A

up to 40%

particularly in western populations

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3
Q

What is the spectrum of allergic diseases?

A
  • atopic dermatitis (eczema)
  • asthma
  • food allergy
  • allergic rhinitis
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4
Q

Is there a rising prevalence of immune disorders?

A
  • 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

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5
Q

What is sensitisation?

A

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

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6
Q

What is anaphylaxis? How have rates of anaphylaxis changed ?

A

most severe form of allergy

250% increase in total anaphylaxis

  • 230% increase in non-food anaphylaxis
  • 350% increase in food anaphylaxis
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7
Q

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

A
  • 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)
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8
Q

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

A
  • peanuts (328% increase)
  • treenuts and seeds
  • fish
  • crustaceans
  • eggs
  • milk products (154%)
  • fruits, vegetables
  • food additives
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9
Q

What are determinants of allergic disease?

A
  • 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
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10
Q

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

A

microbial exposure

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

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11
Q

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

A
  • 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
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12
Q

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

A
  • 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
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13
Q

What would a normal immune response be, simplistically?

A

Th1 Th2 balance with Th1 healthy response

lack of reg function can lead to Th2 skewed response

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14
Q

What is altered in allergic children?

A
  • intestinal microbiota
  • lower levels of probiotic bacteria (e.g. lactobacillus and bifidobacteria)
  • higher levels of pathogenic bacteria (e.g. Staphylococcus aureus and Clostridium difficile)
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15
Q

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

A
  • 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)
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16
Q

When do these changes occur?

A
  • precede the development of allergic disease
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17
Q

What do we see in children who develop allergic disease?

A
  • lower counts bifidobacteria at 1 mos and bacteroides at 12 mos
  • less often colonised with enterococci at 1 mos and bidifobacteria at 1 year
    AND
  • higher counts of clostridia in first weeks and at 3 months
  • more often colonised with staphylococcus at 6 mos
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18
Q

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

A

3 - 6 months

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19
Q

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

A
  • healthy intestinal microflora plays a critical role in the maturation of the immune system and development of tolerance required to avert allergic response
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20
Q

What are strategies to promote a healthy microbial flora?

A
  • may offer novel approaches to prevention or treatment
  • probiotics
  • diet
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21
Q

What is the incidence of food allergy?

A
  • 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
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22
Q

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

A

> 90% of food is caused by

  • cow’s milk
  • hen’s egg
  • peanut
  • tree nuts
  • fish
  • wheat
  • shellfish
  • soya bean
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23
Q

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

A
  • peanut, fish and shellfish (only about 20% resolution by 5yo cf 80% of other food allergens)
24
Q

What are common food allergens in children and adults?

A

Children

  • egg, milk, peanut
  • soy, wheat, fish

Adults

  • peanut, tree nuts, fish, shellfish
  • more serious in nature
25
Q

What do we talk about when talking about allergy?

A

predominantly IgE mediated

26
Q

What kinds (?) of allergy are there?

A
  • IgE mediated
  • Non IgE mediated (unknown aetiology type basis, distinct mechanism)
  • mixed
27
Q

When does onset of IgE mediated allergy occur?

A

< 30 minutes - 1 hour

generally occur very quickly

28
Q

What does an allergic reaction involve? (re systems)

A

systemic reactions

skin 
- erythema 
- urticaria 
- angiodema 
- eczema
gut
- vomiting 
- diarrhoea
- cramps 
resp
- cough
- sneezing 
- stridor wheeze
- hoarse voice 
CVS
- hypotension
29
Q

What is urticaria?

A

hives

  • characteristic rash that can occur all over the body
  • hours to days
30
Q

What is angioedema?

A
  • dilatation of capillaries around eyes and lips
31
Q

If angioedema occurs very quickly what would this indicate?

A

food allergy

32
Q

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

A
  • hoarse voice
  • difficulty swallowing
  • feeling of tightness in the throat
  • persistent coughing
  • noisy breathing - stridor and/or wheeze
  • difficulty breathing
33
Q

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

A
  • drowsy
  • collapse
  • pale and floppy (infant or young child)
34
Q

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

A
  • allergen avoidance
  • education
    • recognition and management of allergic reactions and anaphylaxis
    • action plan
  • adrenaline autoinjector
35
Q

Do we have treatment/cure for food allergy?

A

no cure

- limited treatment except for adrenalin shot

36
Q

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

A

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
37
Q

What are mucosal immune responses?

A

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

38
Q

How is food allergy considered a loss of tolerance?

A
  • 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

39
Q

What does an immune response look like in food allergy?

A
  • 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
40
Q

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

A

desensitisation

  • 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
41
Q

How do we measure desensitisation and tolerance?

A
  • 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
42
Q

What are immunological effects of immunotherapy?

A
  • 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
43
Q

What were the early forms of immunotherapy for food allergy?

A

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
44
Q

What is oral immunotherapy for food allergy?

A

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

45
Q

How do we know that OIT works for desensitisation?

A

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)
46
Q

Can OIT induce tolerance?

A
  • 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)
47
Q

So what is OIT able to induce?

A

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

48
Q

What are the existing protocols for OIT for food therapy?

A
  • low doses of allergen: <1 year
49
Q

What was seen in long term follow up of OIT?

A

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
50
Q

How could the effectiveness of OIT be enhanced?

A
  • higher maintenance dose?

- inclusion of an adjuvant?

51
Q

What are adjuvants in immunotherapy?

A

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
52
Q

What is PPOIT?

A
  • 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
53
Q

How many people are affected by food allergy?

A
  • food allergy affects up to 10% of children and 2% of adults, and burden is rising exponentially
54
Q

What are current major issues re: allergy?

A
  • currently no effective treatment
  • avoidance is difficult to achieve
  • substantial impact on quality of life
55
Q

What treatments have been trialled?

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

PATH30001 (34 decks)

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