THE MICROBIOME AND FOOD ALLERGIES - PRESENTED BY WAYNE SHREFFLER, MD PHD JUNE 2020 - FOOD ALLERGY RESEARCH ...
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The Microbiome and Food Allergies Presented by Wayne Shreffler, MD PhD June 2020
Today’s Presenter
Wayne Shreffler, MD PhD
Chief, Pediatric Allergy & Immunology
Director, Food Allergy Center
Principal Investigator, Center for Immunology &
Inflammatory Diseases
Massachusetts General Hospital
2
Disclosures § Aimmune Therapeutics – Scientific Advisory Board § FARE – Medical Advisory Board § Bulmann Laboratories AG – Consulting § Sanofi USA – Consulting § Vedanta Biosciences – Research support § NIAID – Research support § Food Allergy Science Initiative / Broad Institute – Research support § Massachusetts General Hospital -- Employer
Disclosures
Overview
§ Food allergy 101
• Epidemiology, hygiene and tolerance
§ Cohort studies indirectly suggesting a role for the microbiome
§ Building the case for the importance of the microbiome
• Association, Functional, Intervention (in progress)
§ Why it matters and what the future may bring
• ‘Sutton’s Law’, Prevention, Secondary Prevention and Treatment
§ Questions
5
Food allergy 101: Epidemiology Fig. 1. The percentage of children 0e17 years of age in the United States with a reported allergic condition in the past 12 months; 1997e2011. From Jac
Health Services Data Brief #121; May 2013.
H.A. Sampson / Allergology International 65 (2016) 363e369 365
dren 0e17 years of age in the United States with a reported allergic condition in the past 12 Fig.
months; 1997e2011. From
2. Food-induced Jackson
hospital KD et al.admissions
anaphylaxis National Child
Jackson KD et al. National Child Health Services Data Brief #121;
21; May 2013.
May 2013 Liew WK et al. JinAllergy
Australia by age group from 1994 to 2005. From WK Liew et al. J Allergy Clin Immun
Clin Immunol 2009; 123:434e42
IgE in the serum and the likelihood that a patient would react to a food challenges, whereas today oral food
specific food.28,29 Since then, numerous studies in different patient accepted “gold standard”27,39 and efforts hav
populations have been undertaken in an attempt to refine the dardize the procedure worldwide.15
diagnostic accuracy of quantitative serum food-specific IgE mea- For decades allergists and clinicians have
surements.30,31 More recently, the advent of quantitative IgE mea- young infants “outgrow” their food allergie
Sampson HA. Allergol Int. 2016 Oct;65(4):363–9. surements to major allergenic proteins within certain foods, e.g. Ara such as milk, egg, soy and wheat, whereas a
h 2 in peanut32,33 and Cor a 9 and 14 in hazelnut,34,35 has further e.g. peanuts, tree nuts and seafood, are m
improved the diagnostic accuracy of in vitro testing. In the mid- throughout life. However, it was not until 6
Food allergy 101: Epidemiology
FIGURE 3
Comparing rates of parent-reported versus convincing versus physician-confirmed FAs.
cohort, and higherGupta
Lieberman J, et al.Ann Asthma All Immunol; 2018121(5):S13. than Sicherer for FA diagnosis,
RS, et al. Pediatrics. such methods issue resulting in relatively high
2018 Dec;142(6):e20181235.
20
et al’s national estimate of 1.4% were not employed in the current rates of severe allergic reactions and
in 2008. Although our data suggest study because of their expense, ED use. Previous findings of racial7
Food allergy 101: Epidemiology
| MOTOSUE ET al .
Motosue MS, et al. Pediatr Allergy Immunol. 2018 Aug;29(5):538–44.
Pediatric food-induced anaphylaxis emergency department visit rates by trigger, 2005-2014 [Colour figure can be viewed at
wileyonlinelibrary.com]
| In our cohort, whereas rates of FIA-related ED visits increased, 8
features closely resemble those of seizures reported in malignanit phase of' hypertension: experimental cvidence from the hyper-
/bmj.299.6710.1259 on 18 November 1989. Downloaded from http://www.b
tensive rat. Iancct 1954;ii:201-1 1.
patients treated with erythropoietin while undergoing
dialysis.2 As with erythropoietin, the factors precipitat-
Food allergy 101: The Hygiene Hypothesis
Accepted 25 August 1989)
Hay fever, hygiene, and report of "hay fever or allergic rhinitis in the past
12 months" at age 11; (c) parental recall of "eczema in
household size the first year of life" elicited when the child was 7.
Cross tabulations were performed with the SAS
statistical package, and multiple logistic regression
David P Strachan models“Over the
were fitted withpast century
the LR program in the declining
BMDP
statistical package.
Hay fever has been described as a "post industrial Of family size, improvements
the 16 perinatal, social, and environmentalin
revolution epidemic,"' and successive morbidity factorshousehold amenities,
studied the most striking associationsand
with hayhigher
surveys from British general practice suggest that its fever were those for family size and position in the
prevalence has continued to increase over the past 30
years.) Other evidence suggests a recent increase in the
standards
household in childhood.of Thepersonal
table shows thatcleanliness
at both
11 and 23 years of age hay fever was inversely related to
prevalence of asthma2 and childhood eczema.3 This haveofreduced
the number children in thethe opportunity
household at age 11 for
paper suggests a possible explanation for these trends (when it is assumed most families were complete).
over time. Whencross infection
prevalence figures were in young
adjusted families.”
by multiple
logistic regression for other significant determinants of
hay fever in this cohort (see table) the associations with
Subjects, methods, and results numbers of older and younger children in the household
I studied the epidemiology of hay fever in a national persisted. These trends in adjusted prevalence were
StrachanofDP.
sample 414 British
17 BMJ. children
1989 Nov born during one week
18;299(6710):1259–60. independent of one another and each was significant
in March 1958 and followed up to the age of 23 years (p
PERSPECTIVE Food allergy 101: The Hygiene Hypothesis (Plus)
• Breast milk • Infant formula
• Raw cow’s milk
Skin
microbiome
Nasopharynx
microbiome
Lung
microbiome
Gut
• Mode of delivery microbiome
• Maternal diet
• Maternal antibiotics • Infection history
• Antibiotic use
• Vaccination
Debbie Maizels/Springer Nature
• ‘Time window’
• Organ development
• Immune system
development
• Family size
• Sibship order
• Close contact with pets
• Daycare attendance
and farm animals
Figure 1 Protective and risk factors for allergy development in early life. Many of the risk factors for allergic disease affect the microbiome of the skin,
Lambrecht BN, Hammad H. Nat Immunol. 2017 Sep 19;18(10):1076–83.
nasopharynx, lung and gut, particularly in a critical window in the early postnatal period when these organs, as well as the immune system, are still
developing. Infections can have both protective and detrimental effects on allergy. Often these factors occur together, so the absence of one protective
factor does not necessarily mean that allergic disease will ensue. Also, many risk factors are associated. Antibiotic use is hard to disentangle from
10
infection history.Food allergy 101: Glossary
§ MICROBIOME: The sum of microbes and their § PROBIOTIC: Live microorganisms with
genomic elements in a particular beneficial effects on the host.
environment. § PREBIOTIC: Nondigestible substrates that
§ SHORT-CHAIN FATTY ACID: Fatty acids with promote the growth, function, or both of
fewer than 6 carbon atoms. beneficial microorganisms.
§ RORɣt+ Treg CELLS: Also referred to as type 3 § DYSBIOSIS: A state of imbalance in a
regulatory T (Treg) cells, these Foxp3+ Treg microbial ecosystem.
cells are generated in response to the
intestinal microbiota and are essential for
suppression of type 2 immunity.
Bunyavanich S, Berin MC. J Allergy Clin Immunol. 2019 Dec;144(6):1468–77.
11od allergy 3,4,109. IgE116. Dietary nutrients might exert influences on the
r other specific composition of the gut microbiome; GPCRs and other
ation as studies receptors might sense compounds present in the intes-
y, a wide range Food allergy 101: The tolerance paradigm
tinal lumen and absorbed across the epithelium (such as
b Tolerance breakdown Healthy
Goblet Allergen Bacteria Unhealthy (Dysbiosis)
Intestinal
SCFA
cell Damaged cell lumen
CX3CR1+ PAMPs Intestinal
macrophage mucosa
IL-10 IL-25
ILC2
IL-33
TSLP
IgE
Treg FcεRI
T H2 IL-4
TGFβ
Mast cell
IL-4 B
Treg
IL-13 cell
ell
wn of tolerance to ingested antigens. a | Under normal
Nature conditions,
Reviews food
| Disease Primers
into the intestinal mucosa or into Peyer patches (small masses of lymphatic
nterocytes or by active transport through enterocytes, microfold (M) cells or
by specialized CX3C-chemokine receptor 1 (CX3CR1)+ macrophages that
Modified from Renz H, et al.+ Food allergy. Nat Rev Dis Primers. 2018 Jan 4;4:17098–20.
dendritic cells in the lamina propria. These cells
β (TGFβ) productionOverview
§ Food allergy 101
• Epidemiology, hygiene and tolerance
§ Cohort studies indirectly suggesting a role for the microbiome
§ Building the case for the importance of the microbiome
• Association, Functional, Intervention (in progress)
§ Why it matters and what the future may bring
• ‘Sutton’s Law’, Prevention, Secondary Prevention and Treatment
§ Questions
13Observational cohort studies (allergy generally)
§ Prenatal maternal exposure to pets
§ Birth by vaginal versus cesarean section delivery
§ Growing up in rural environment (close contact with animals)
§ Growing up with pets (or older siblings)
Aichbhaumik N, et al. Clin Exp Allergy 2008;38:1787-94.
Bager P, et al. Clin Exp Allergy 2008;38:634-42.
von Mutius E, Radon K. Immunol Allergy Clin North Am 2008;28:631-47
Ownby DR, et al. JAMA 2002;288: 963-72.
Kim H, et al. Curr Allergy Asthma Rep 2019;19:22.
14outcomes. Overall, delivery by c-section was associated inhalant atopy or eczema/atopic dermatitis. Taking
with a significantly increased summary OR of food into account the significant heterogeneity between the
Observational cohort studies specific to food allergy
allergy/food atopy, allergic rhinitis, asthma, and hospita- study-specific relative risks for asthma (P o 0.01), and
lized asthma, whereas there was no association with hospitalization for asthma (P o 0.01) using the ran-
Bager P, et al. Clin Exp Allergy. 2008 Apr;38(4):634–42.
15Observational cohort studies specific to food allergy
Koplin JJ, et al. Allergy. 2012 Nov;67(11):1415–22.
163 years
2 years
18 months
Blood Draw
9mo 1 year
6mo Stool Sample
4mo
2mo Study Visit
1mo
2wk
1wk
Prospective Observational Infant Cohort Study n=10034 MARTIN ET AL
Observational cohort studies: GMAP J ALLERGY CLIN IMMUNOL PRACT
MONTH 2020
Martin VM, et al. J Allergy Clin Immunol Pract. 2020 May;8(5):1692–1699.e1.
18J ALLERGY CLIN IMMUNOL PRACT
Observational cohort studies: GMAP MARTIN ET AL 5
VOLUME -, NUMBER -
Initial Diet Diet over Time
0.25
0.25
Formula (F)
Formula (F)
0.20
0.20
Proportion with FPIAP
Proportion with FPIAP
Breastmilk (B)
0.15
0.15
Breastmilk (B)
0.10
Mixed (M)
0.10
Mixed (M)
0.05
0.05
Hazard Ratios [95% CI], p-value Hazard Ratios [95% CI], p-value
B v. F: 0.47 [0.26, 0.86], p=0.0140 B v. F: 0.63 [0.40, 0.98], p=0.0398
M v. F: 0.39 [0.20, 0.75], p=0.0051 M v. F: 0.44 [0.24, 0.78], p=0.0054
0.00
0.00
M v. B: 0.82 [0.52, 1.29], p=0.3900 M v. B: 0.62 [0.38, 1.00], p=0.0497
0 .5 1 2 0 .5 1 2 3 4
Age (months) Age (months)
Number at risk Number at risk
Formula 59 55 51 46 Formula 59 55 79 94 127
A B
Breastmilk 558 553 530 495 Breastmilk 558 553 566 493 449
Mixed 286 282 271 259 Mixed 286 282 191 197 177
FIGURE
Martin3.VM,
Effect
et al. of infantClin
J Allergy dietImmunol
on FPIAP development.
Pract. (A) Kaplan-Meier curves of time to FPIAP diagnosis by infant initial diet.
2020 May;8(5):1692–1699.e1.
(B) Kaplan-Meier curves of time to FPIAP diagnosis by infant diet as a time-varying covariate over the first 4 months (during
which 95% of FPIAP cases presented). 19Observational cohort studies: GMAP
20Overview
§ Food allergy 101
• Epidemiology, hygiene and tolerance
§ Cohort studies indirectly suggesting a role for the microbiome
§ Building the case for the importance of the microbiome
• Association, Functional, Intervention (in progress)
§ Why it matters and what the future may bring
• ‘Sutton’s Law’, Prevention, Secondary Prevention and Treatment
§ Questions
211470 BUNYAVANICH AND BERIN J ALLERGY CLIN IMMUNOL
Hierarchy of Evidence DECEMBER 2019
Observa!onal Func!onal Analysis Interven!on
Food Clinical Trial
Healthy Allergic
Randomized
Placebo Microbial
Control Therapeutic
Diet
Probio!cs
in vitro
immune
modulation Prebio!cs
Resistant Susceptible
FMT + Synbio!cs
Susceptible Germ-Free Mice Fecal Microbial
Transfer
Food Allergy Outcome
Microbial Composition Transmission of Resistance
Bunyavanich S, Berin MC. J AllergyFIG Pathways to
1. Immunol.
Clin the development
2019 of microbial therapeutics for food allergy. Evidence for an important
Dec;144(6):1468–77.
contribution of the gut microbiota to the pathogenesis of food allergy is derived from observational studies
of distinct microbial composition in allergic and healthy human cohorts, and in mice with susceptibility
22
versus resistance to food allergy. Evidence that changes in microbial composition lead to meaningfulEgg allergy and egg sensitization Fazlollahi M, et al. Allergy. 2018 Jul;73(7):1515–24.
Egg allergy and egg sensitization
Egg sensitization
Fazlollahi M, et al. Allergy. 2018 Jul;73(7):1515–24.The IL4raF709 OVA model
Clostridiales
Noval Rivas M, et al. J Allergy Clin Immunol. 2013 Jan;131(1):201–12.Persistent vs transient milk allergy No associations with mode of delivery, antibiotics, breast-feeding, AD Bunyavanich S, et al. J Allergy Clin Immunol. 2016 Oct;138(4):1122–30.
Persistent vs transient milk allergy Bunyavanich S, et al. J Allergy Clin Immunol. 2016 Oct;138(4):1122–30.
1470 BUNYAVANICH AND BERIN J ALLERGY CLIN IMMUNOL
Hierarchy of Evidence DECEMBER 2019
Observa!onal Func!onal Analysis
Functional Analysis Interven!on
Food Clinical Trial
Healthy Allergic
Randomized
Placebo Microbial
Control Therapeutic
Diet
Probio!cs
in vitro
immune
modulation Prebio!cs
Resistant Susceptible
FMT + Synbio!cs
Susceptible Germ-Free Mice Fecal Microbial
Transfer
Food Allergy Outcome
Microbial Composition Transmission of Resistance
Bunyavanich S, Berin MC. J AllergyFIG Pathways to
1. Immunol.
Clin the development
2019 of microbial therapeutics for food allergy. Evidence for an important
Dec;144(6):1468–77.
contribution of the gut microbiota to the pathogenesis of food allergy is derived from observational studies
of distinct microbial composition in allergic and healthy human cohorts, and in mice with susceptibility
28
versus resistance to food allergy. Evidence that changes in microbial composition lead to meaningfulFood allergic infants: human to murine model § 56 infants with food allergy* § 98 age-matched non-allergic controls § Sampled at multiple timepoints from 1 to 30 months § 16S but with higher resolution OTU picking § Functional studies by fecal transplantation * ‘to at least one of the major food allergens including milk, soy, egg, tree nuts, fish, shellfish, wheat, or peanuts’ Abdel-Gadir A, et al. Nat Med. 2019 Jul;25(7):1164–74.
Food allergic infants: human to murine model
Lachnospiraceae Other Clostridales
Subdoligranulum
Abdel-Gadir A, et al. Nat Med. 2019 Jul;25(7):1164–74.Food allergic infants: human to murine model 2
§ 4 infants with milk allergy
§ 4 age-matched non-allergic controls
§ Sampled once during infancy
§ 16S but with high resolution OTU picking
§ Functional studies by fecal transplantation
Feehley T, et al. Nat Med. 2019 Mar;25(3):448–53.Food allergic infants: human to murine model number 2 Feehley T, et al. Nat Med. 2019 Mar;25(3):448–53.
Food allergic infants: human to murine model number 2 Feehley T, et al. Nat Med. 2019 Mar;25(3):448–53.
Hierarchy of Evidence
Bunyavanich S, Berin MC. J Allergy Clin Immunol. 2019 Dec;144(6):1468–77.
34Clinical trials
§ Probiotics for Cow’s Milk Allergy
• 119 infants with CMA, L. casei and B. lactis did not accelerate tolerance
• 55 infants with EHCF and L rhamnosus GG (LGG) did resolve sooner
• 220 infants with EHCF and LGG resolved CMA at higher rates during follow
up to 3 years
• Response associated with changes in frequency of butyrate producing
organisms
§ LGG as adjuvant to peanut OIT (Tang et al): at 4 years follow up, 67% v
4% actively consuming peanut
• Larger follow up study with OIT alone arm in progress
Fazlollahi M, et al. Allergy. 2018 Jul;73(7):1515–24.
35Clinical trials
§ NCT02960074 Boston Children’s Hospital, Rima Rachid
§ NCT03936998 MGH-Vedanta Biosciences, Wayne Shreffler
https://www.foodallergy.org/resources/fare-clinical-network-centers-distinction
36than minor members of the intestinal microbiota in exGF mice inocu- plementary Fig. 3). In mi
lated with chloroform-treated human faeces drive the observed induc- OTUs belonging to Bact
tion of Treg cells (Fig. 1e). The Treg-cell-inducing microbiota in mice caecal microbial commu
exGF mice inoculated w
Clinical trials inoculated with the 2 3 104-fold diluted sample (12 3 104 mice) was a
stable community, because serial oral inoculation of caecal contents related to Clostridia spec
and 1(2 3 104)2 mice ha
about 20 species of Clostr
Correspo.
a b Closest species/strain strain no. To isolate bacterial str
LETTER doi:10.1038/nature12331
Bacteroidetes
Clostridia
Others Clostridium clostridioforme
Oscillibacter valericigenes
Hydrogenoanaerobacterium
-
-
-
cultured caecal contents fr
mice in vitro and picked
100 saccharovorans gene sequences of the isol
Clostridium asparagiforme St 15 were present, all of which
Treg induction by a rationally selected mixture of
Relative abundances of OTUs (%)
90 Anaerotruncus colihominis St 13
Clostridiaceae JC13 St 8 the 31 strains, we selected
80
Clostridia strains from the human microbiota 70
Clostridium bolteae
Clostridiales 1_7_47FAA
St 7
St 28
sequence identity to any o
We then individually cu
Lachnospiraceae 7 1 58FAA St 3
Koji Atarashi 1,2,3 1,2 4,5 5
*, Takeshi Tanoue *, Kenshiro Oshima *, Wataru Suda , Yuji Nagano , Hiroyoshi Nishikawa , Shinji Fukuda , 1,2 6 1,7
60 Clostridium scindens St 26 amounts, and orally inoc
17 strains
Takuro Saito6, Seiko Narushima1, Koji Hase1,3, Sangwan Kim5, Joëlle V. Fritz8, Paul Wilmes8, Satoshi Ueha9, Kouji Matsushima9, Clostridium 7 3 54FAA St 16
Hiroshi Ohno , Bernat Olle10, Shimon Sakaguchi6, Tadatsugu Taniguchi2, Hidetoshi Morita4,11, Masahira Hattori5
1
50
(123-mix mice). Numer
Ruminococcus sp. ID8 St 14
& Kenya Honda1,2,4
Clostridium indolis St 9 observed by scanning elec
40
Eubacterium fissicatena St 21 surface in 123-mix mice
30 Clostridium ramosum St 18
Manipulation of the gut microbiota holds great promise for the immune responses in the mouse small intestine8, we observed a signifi-
Lachnospiraceae 3_1_57FAA St 29
caeca were quite differen
treatment of inflammatory and allergic diseases1,2. Although numer- cant increase in the percentage of FOXP31 Treg cells among CD41
ous probiotic microorganisms have been identified3, there remains T cells in the colons of exGF mice inoculated with untreated human 20 Clostridium sp. 14774 St 1 successful colonization (S
a compelling need to discover organisms that elicit more robust thera- faeces compared with germ-free mice (Fig. 1a and Supplementary Fig. 2). Lachnospiraceae 3_1_57FAA St 27 16S rRNA genes revealed
10
peutic responses, are compatible with the host, and can affect a specific Notably, a more pronounced increase was observed in the colons Blautia producta St 6
arm of the host immune system in a well-controlled, physiological of exGF mice inoculated with chloroform-treated human faeces 0 Clostridium hathewayi St 4 123-mix mice was quite
manner. Here we use a rational approach to isolate CD41FOXP31 (Fig. 1a). These findings suggest that the human intestinal microbiota In 123-mix mice, we obs
2× re
u
+2 o
×1 0 4
+2 4) 2
ix
+h
hl
m
regulatory T (Treg)-cell-inducing bacterial strains from the human
-
contains Treg-cell-inducing bacteria, and that they are enriched in
04
+2 ×1
uC
10
colonic lamina propria (F
3-
indigenous microbiota. Starting with a healthy human faecal sample, the chloroform-resistant fraction. We also examined the effects of human
+h
a sequence of selection steps was applied to obtain mice colonized with faeces inoculation on colonic IL-17- and IFN-c-expressing CD41 that observed in exGF
+(
human microbiota enriched in Treg-cell-inducing species. From these cells (TH17 and TH1 cells). In exGF mice inoculated with untreated or
mice, we isolated and selected 17 strains of bacteria on the basis of chloroform-treated human faeces, the frequency of TH1 cells was c +23-mix d e human faeces and much
Helios– in FOXP3 (%)
their high potency in enhancing Treg cell abundance and inducing unchanged compared with germ-free mice (Fig. 1b). By contrast, there 60 100 Faecalibacterium prausni
FOXP3+ in CD4 (%)
important anti-inflammatory molecules—including interleukin-10 ** **
(IL-10) and inducible T-cell co-stimulator (ICOS)—in Treg cells upon
a b c 80 for enhancing regulatory
inoculation into germ-free mice. Genome sequencing revealed that 40 **
20 20 40 123-mix mice expressed
NS NS 60
FOXP3+ in CD4 (%)
IL-17+ in CD4 (%)
IFN-γ+ in CD4 (%)
the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, ** NS NS
30 ** ** **
which lack prominent toxins and virulence factors. The 17 strains
40 indicating antigen-experi
act as a community to provide bacterial antigens and a TGF-b-rich 20 10 10 20
environment to help expansion and differentiation of Treg cells. 20 and ref. 10).
10
Oral administration of the combination of 17 strains to adult mice
0 0 0 0 0 Only 17 strains listed
attenuated disease in models of colitis and allergic diarrhoea. Use of
detected in 123-mix mic
e
+F hlo
+h mix
li.
+2 ree
o
e
e
e
+h mix
+h h u
o
u
o
u
o
the isolated strains may allow for tailored therapeutic manipulation
fre
fre
fre
fre
+h
+h
hl
hl
hl
hl
ca
+
uC
uC
uC
Atarashi K, et al. Nature; 2013 Jul 30;500(7461):232–6.
uC
m
m
m
uC
f
3-
of human immune disorders. that these 17 strains may
3-
ae
m
+h
+h
er
er
er
m
+2
G
G
G
er
er
CD41FOXP31 Treg cells are present most abundantly in the intest-
G
d e
G
inal mucosa at steady state, and contribute to intestinal and systemic 60 ** 60
**
found that the mixture o
3+ in CD4 (%)
3+ in CD4 (%)
immune homeostasis4–7. In germ-free mice, the frequency of colonic Treg ** ** ** ** **
40 40
Figure 2 | Assessment of microbiota composition and isolation of Treg-cell- cells to a similar extent as
cells and levels of IL-10 expression by Treg cells are markedly reduced4–7.
We have shown previously that a combination of Clostridia strains inducing strains. a, b, Pyrosequencing of 16S rRNA genes was performed on induced by the 17-mix 37 w
20 20Clinical trials: NCT03936998
VE416 Phase Ib/II in Peanut Allergy- Plan Final
Phase Ib Phase II Post-Phase II Maintenance
---------------------------------------------------------------------------- 55 weeks ---------------------------------------------------------------------------------------
Age 12-55* (10 / group)
--- 7 weeks --- 1 wk --- 6 -10 w build up ---- -------- 10 w maint ------ 1 wk ------ 24 weeks -------- 1 wk
Age 12-55
Inclusion: tolerates at least
VE416 300 mg (430 mg cumulative)
Active Vanc Cohort 1 PNOIT maintenance
Entry DBPCFC (143 mg) Phase
x5d
x 6 (10) PBO PBO + PNOIT (à randomized 1:1)
(10) (40 mg) + PBO
wks
DBPCFC1 (5030 mg)
DBPCFC2 (5030 mg)
II Inclusion:Wait! What about the skin??
Staph, Staph, Staph (?)
39Other research
§ Basic mucosal immunology and food science
• The mechanisms of sensing the diet are complex and poorly understood
with myriad sensors utilized by specialized epithelial cells, immune cells
and neuronal cells all likely sensing both bioactive components of food and
metabolites of the microbiome
§ Non-IgE-mediated food allergies, such as FPIES, EoE and FPIAP
§ Role of microbiome in shaping the immune repertoire and metabolizing
food proteins
§ Impact of OIT on microbiome and relationship to outcomes
§ Much more to come!!
40Potential impact: does the Willie Sutton rule apply?
§ The most obvious intervention would seem to be the one that is most
likely to address the tolerance paradigm
§ Prevention, Secondary Prevention and Treatment
41Evidence of Treg induction by OIT to food Ag Syed A, et al. J Allergy Clin Immunol. 2014;133(2):500–10. Varshney P, et al. J Allergy Clin Immunol. 2011;127(3):654–60.
Overview
§ Food allergy 101
• Epidemiology, hygiene and tolerance
§ Cohort studies indirectly suggesting a role for the microbiome
§ Building the case for the importance of the microbiome
• Association, Functional, Intervention (in progress)
§ Why it matters and what the future may bring
• ‘Sutton’s Law’, Prevention, Secondary Prevention and Treatment
§ Questions
43Evidence of Treg induction by OIT to food Ag – or not?
Wambre E, et al. Sci Transl Med. 2017 2;9(401):eaam9171.
Ryan JF, et al. PNAS USA. 2016 Mar 1;113(9):E1286–95. Frischmeyer-Guerrerio PA, et al. J Allergy Clin Immunol. 2017A key role for neutralizing antibodies Patil SU, et al. J Allergy Clin Immunol. 2019 Aug 1.
Thank you and acknowledgments
§ Citations throughout – recommend recent review by Bunyanavich and
Bern, JACI Dec 2019
§ Research support from:
• NIAID/CoFAR, Demarest Lloyd Foundation, Gerber Foundation, Food Allergy
Science Initiative, EAT, Vedanta Biosciences
§ Key collaborators:
• MIT/FASI: Chris Love
• MGH: Sarita Patil, Qian Yuan, Tori Martin, Yamini Virkud, Robert Anthony
• FARE Discovery Center: Rima Rachid, Chen Rosenberg, Joyce Hsu
46Question & Answer
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