Background: Wheat is known as the most widely consumed food all over the world. Although many types of wheat allergy have been recognized, their treatment still has a long way to go due to the complex pathogenesis. Oral immunotherapy (OIT) is under investigation for the treatment of wheat allergies. Previous studies have demonstrated that OIT using intact wheat allergens can induce tolerance, but is accompanied by a high risk of anaphylactic reactions. Objectives: Our objective was to prepare modified wheat allergens with hypoallergenic and tolerance-inducing properties to reduce adverse effects during immunotherapy. Methods: Wheat gliadin was degraded by hydrolysis with pepsin and trypsin, and then the hydrolysate was deamidated with hydrochloric acid. The IgE-binding capacity and T cell reactivity of the degraded gliadins were evaluated in vitro. Pepsin-digested gliadin (peptic-GLI) was applied in a mouse model to investigate whether it would induce oral tolerance. Results: Degradation with pepsin decreased IgE-binding capacity and maintained T cell reactivity. Oral administration of peptic-GLI to mice before sensitization and challenge with gliadin could significantly suppress the production of IgE, IgG1, and type 2 T helper cytokines. Moreover, the development of anaphylactic reactions and allergic responses of the small intestine induced by gliadin challenge were inhibited by oral administration of peptic-GLI. Conclusions: The findings of this study indicate that peptic-GLI with low allergenicity and potential for tolerance induction may become useful in wheat immunotherapy with less adverse effects.

1.
Keet
CA
,
Matsui
EC
,
Dhillon
G
,
Lenehan
P
,
Paterakis
M
,
Wood
RA
.
The natural history of wheat allergy
.
Ann Allergy Asthma Immunol
.
2009
May
;
102
(
5
):
410
5
.
[PubMed]
1081-1206
2.
Burks
AW
,
Laubach
S
,
Jones
SM
.
Oral tolerance, food allergy, and immunotherapy: implications for future treatment
.
J Allergy Clin Immunol
.
2008
Jun
;
121
(
6
):
1344
50
.
[PubMed]
0091-6749
3.
Mousallem
T
,
Burks
AW
.
Immunology in the Clinic Review Series; focus on allergies: immunotherapy for food allergy
.
Clin Exp Immunol
.
2012
Jan
;
167
(
1
):
26
31
.
[PubMed]
0009-9104
4.
Utsunomiya
T
,
Imai
T
,
Ogura
K
,
Goto
M
,
Likura
K
,
Koike
Y
, et al
Rush oral immunotherapy for wheat induced anaphylaxis in Japan
.
J Allergy Clin Immunol
.
2012
Feb
;
129
(
2
):
AB26
. 0091-6749
5.
Sato
S
,
Utsunomiya
T
,
Imai
T
,
Yanagida
N
,
Asaumi
T
,
Ogura
K
, et al
Wheat oral immunotherapy for wheat-induced anaphylaxis
.
J Allergy Clin Immunol
.
2015
Oct
;
136
(
4
):
1131
3.e7
.
[PubMed]
0091-6749
6.
Pacharn
P
,
Siripipattanamongkol
N
,
Veskitkul
J
,
Jirapongsananuruk
O
,
Visitsunthorn
N
,
Vichyanond
P
.
Successful wheat-specific oral immunotherapy in highly sensitive individuals with a novel multirush/maintenance regimen
.
Asia Pac Allergy
.
2014
Jul
;
4
(
3
):
180
3
.
[PubMed]
2233-8276
7.
Tatham
AS
,
Shewry
PR
.
The conformation of wheat gluten proteins. The secondary structures and thermal stabilities of α-, β-, γ- and ω-gliadins
.
J Cereal Sci
.
1985
Apr
;
3
(
2
):
103
13
. 0733-5210
8.
Battais
F
,
Mothes
T
,
Moneret-Vautrin
DA
,
Pineau
F
,
Kanny
G
,
Popineau
Y
, et al
Identification of IgE-binding epitopes on gliadins for patients with food allergy to wheat
.
Allergy
.
2005
Jun
;
60
(
6
):
815
21
.
[PubMed]
0105-4538
9.
Inomata
N
.
Wheat allergy
.
Curr Opin Allergy Clin Immunol
.
2009
Jun
;
9
(
3
):
238
43
.
[PubMed]
1528-4050
10.
Kumagai
H
,
Suda
A
,
Sakurai
H
,
Kumagai
H
,
Arai
S
,
Inomata
N
, et al
Improvement of digestibility, reduction in allergenicity, and induction of oral tolerance of wheat gliadin by deamidation
.
Biosci Biotechnol Biochem
.
2007
Apr
;
71
(
4
):
977
85
.
[PubMed]
0916-8451
11.
Abe
R
,
Shimizu
S
,
Yasuda
K
,
Sugai
M
,
Okada
Y
,
Chiba
K
, et al
Evaluation of reduced allergenicity of deamidated gliadin in a mouse model of wheat-gliadin allergy using an antibody prepared by a peptide containing three epitopes
.
J Agric Food Chem
.
2014
Apr
;
62
(
13
):
2845
52
.
[PubMed]
0021-8561
12.
Abe
R
,
Matsukaza
N
,
Yamaguchi
Y
,
Akao
M
,
Kumagai
H
,
Kumagai
H
.
Wheat gliadin deamidated by cation-exchange resins induces oral tolerance in a mouse model of wheat allergy
.
J Food Bioact.
2018
Jun
;
2
(
2
):
119
28
.
13.
Mimouni
B
,
Raymond
J
,
Merle-Desnoyers
AM
,
Azanza
JL
,
Ducastaing
A
.
Combined acid deamidation and enzymic hydrolysis for improvement of the functional properties of wheat gluten
.
J Cereal Sci
.
1994
Sep
;
20
(
2
):
153
65
. 0733-5210
14.
Hoyne
GF
,
Callow
MG
,
Kuo
MC
,
Thomas
WR
.
Inhibition of T-cell responses by feeding peptides containing major and cryptic epitopes: studies with the Der p I allergen
.
Immunology
.
1994
Oct
;
83
(
2
):
190
5
.
[PubMed]
0019-2805
15.
Takagi
H
,
Hiroi
T
,
Yang
L
,
Tada
Y
,
Yuki
Y
,
Takamura
K
, et al
A rice-based edible vaccine expressing multiple T cell epitopes induces oral tolerance for inhibition of Th2-mediated IgE responses
.
Proc Natl Acad Sci USA
.
2005
Nov
;
102
(
48
):
17525
30
.
[PubMed]
0027-8424
16.
Hacini-Rachinel
F
,
Vissers
YM
,
Doucet-Ladevéze
R
,
Blanchard
C
,
Demont
A
,
Perrot
M
, et al
Low-allergenic hydrolyzed egg induces oral tolerance in mice
.
Int Arch Allergy Immunol
.
2014
;
164
(
1
):
64
73
.
[PubMed]
1018-2438
17.
Hong
SJ
,
Michael
JG
,
Fehringer
A
,
Leung
DY
.
Pepsin-digested peanut contains T-cell epitopes but no IgE epitopes
.
J Allergy Clin Immunol
.
1999
Aug
;
104
(
2 Pt 1
):
473
8
.
[PubMed]
0091-6749
18.
Litwin
A
,
Pesce
AJ
,
Fischer
T
,
Michael
M
,
Michael
JG
.
Regulation of the human immune response to ragweed pollen by immunotherapy. A controlled trial comparing the effect of immunosuppressive peptic fragments of short ragweed with standard treatment
.
Clin Exp Allergy
.
1991
Jul
;
21
(
4
):
457
65
.
[PubMed]
0954-7894
19.
Tanaka
M
,
Nagano
T
,
Yano
H
,
Haruma
K
,
Kato
Y
.
Exercise-independent wheat-induced anaphylaxis caused by ω-5 gliadin in mice
.
Int Arch Allergy Immunol
.
2011
;
156
(
4
):
434
42
.
[PubMed]
1018-2438
20.
Tanaka
M
,
Nagano
T
,
Yano
H
,
Matsuda
T
,
Ikeda
TM
,
Haruma
K
, et al
Impact of ω-5 gliadin on wheat-dependent exercise-induced anaphylaxis in mice
.
Biosci Biotechnol Biochem
.
2011
;
75
(
2
):
313
7
.
[PubMed]
0916-8451
21.
Gourbeyre
P
,
Denery-Papini
S
,
Larré
C
,
Gaudin
JC
,
Brossard
C
,
Bodinier
M
.
Wheat gliadins modified by deamidation are more efficient than native gliadins in inducing a Th2 response in Balb/c mice experimentally sensitized to wheat allergens
.
Mol Nutr Food Res
.
2012
Feb
;
56
(
2
):
336
44
.
[PubMed]
1613-4125
22.
Adel-Patient
K
,
Créminon
C
,
Bernard
H
,
Clément
G
,
Négroni
L
,
Frobert
Y
, et al
Evaluation of a high IgE-responder mouse model of allergy to bovine beta-lactoglobulin (BLG): development of sandwich immunoassays for total and allergen-specific IgE, IgG1 and IgG2a in BLG-sensitized mice
.
J Immunol Methods
.
2000
Feb
;
235
(
1-2
):
21
32
.
[PubMed]
0022-1759
23.
Bodinier
M
,
Leroy
M
,
Ah-Leung
S
,
Blanc
F
,
Tranquet
O
,
Denery-Papini
S
, et al
Sensitization and elicitation of an allergic reaction to wheat gliadins in mice
.
J Agric Food Chem
.
2009
Feb
;
57
(
4
):
1219
25
.
[PubMed]
0021-8561
24.
Sato
A
,
Hashiguchi
M
,
Toda
E
,
Iwasaki
A
,
Hachimura
S
,
Kaminogawa
S
.
CD11b+ Peyer’s patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells
.
J Immunol
.
2003
Oct
;
171
(
7
):
3684
90
.
[PubMed]
0022-1767
25.
Komatsu
M
.
Studies on histamine in bronchial asthma
.
[Japanese]
.
Allergy
.
1978
Feb
;
27
(
2
):
67
74
.0105-4538
26.
Pacharn
P
,
Vichyanond
P
.
Immunotherapy for IgE-mediated wheat allergy
.
Hum Vaccin Immunother
.
2017
Oct
;
13
(
10
):
2462
6
.
[PubMed]
2164-5515
27.
Watanabe
M
,
Suzuki
T
,
Ikezawa
Z
,
Arai
S
.
Controlled enzymatic treatment of wheat proteins for production of hypoallergenic flour
.
Biosci Biotechnol Biochem
.
1994
Feb
;
58
(
2
):
388
90
. 0916-8451
28.
Watanabe
J
,
Tanabe
S
,
Watanabe
M
,
Kasai
T
,
Sonoyama
K
.
Consumption of hypoallergenic flour prevents gluten-induced airway inflammation in Brown Norway rats
.
Biosci Biotechnol Biochem
.
2001
Aug
;
65
(
8
):
1729
35
.
[PubMed]
0916-8451
29.
Palosuo
K
.
Update on wheat hypersensitivity
.
Curr Opin Allergy Clin Immunol
.
2003
Jun
;
3
(
3
):
205
9
.
[PubMed]
1528-4050
30.
Wedemeyer
J
,
Tsai
M
,
Galli
SJ
.
Roles of mast cells and basophils in innate and acquired immunity
.
Curr Opin Immunol
.
2000
Dec
;
12
(
6
):
624
31
.
[PubMed]
0952-7915
31.
Valenta
R
,
Ball
T
,
Focke
M
,
Linhart
B
,
Mothes
N
,
Niederberger
V
, et al
Immunotherapy of allergic disease
.
Adv Immunol
.
2004
;
82
:
105
53
.
[PubMed]
0065-2776
32.
Haselden
BM
,
Kay
AB
,
Larché
M
.
Peptide-mediated immune responses in specific immunotherapy
.
Int Arch Allergy Immunol
.
2000
Aug
;
122
(
4
):
229
37
.
[PubMed]
1018-2438
33.
Verhoef
A
,
Alexander
C
,
Kay
AB
,
Larché
M
.
T cell epitope immunotherapy induces a CD4+ T cell population with regulatory activity
.
PLoS Med
.
2005
Mar
;
2
(
3
):
e78
.
[PubMed]
1549-1277
34.
Troncone
R
,
Ferguson
A
.
Gliadin presented via the gut induces oral tolerance in mice
.
Clin Exp Immunol
.
1988
May
;
72
(
2
):
284
7
.
[PubMed]
0009-9104
35.
Matsuo
H
,
Dahlström
J
,
Tanaka
A
,
Kohno
K
,
Takahashi
H
,
Furumura
M
, et al
Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis
.
Allergy
.
2008
Feb
;
63
(
2
):
233
6
.
[PubMed]
0105-4538
36.
Romagnani
S
.
Type 1 T helper and type 2 T helper cells: functions, regulation and role in protection and disease
.
Int J Clin Lab Res
.
1991
;
21
(
2
):
152
8
.
[PubMed]
0940-5437
37.
Kinet
JP
.
The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology
.
Annu Rev Immunol
.
1999
;
17
(
1
):
931
72
.
[PubMed]
0732-0582
38.
Ahrens
R
,
Osterfeld
H
,
Wu
D
,
Chen
CY
,
Arumugam
M
,
Groschwitz
K
, et al
Intestinal mast cell levels control severity of oral antigen-induced anaphylaxis in mice
.
Am J Pathol
.
2012
Apr
;
180
(
4
):
1535
46
.
[PubMed]
0002-9440
39.
Leyva-Castillo
JM
,
Galand
C
,
Kam
C
,
Burton
O
,
Gurish
M
,
Musser
MA
, et al
Mechanical skin injury promotes food anaphylaxis by driving intestinal mast cell expansion
.
Immunity
.
2019
May
;
50
(
5
):
1262
1275.e4
.
[PubMed]
1074-7613
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.