Introduction
Allergic diseases are becoming the focus of attention, as their
incidences as well as severity are increasing
worldwide.1–3 Among the responsible allergens, birch
pollen were identified as the third most-diagnosed allergen for
respiratory allergy,4 and around 70% of patients
allergic to birch also develop a secondary food
allergy.5–7 The symptoms of this so-called
pollen-associated food allergy (PFA) range from nasal, ocular and oral
pruritus and angioedema to severe allergic asthma and
anaphylaxis,6,8–10 which has a comprehensive impact
on personal quality of life, work or school performance and the
socio-economic burden.4,11
In the pathogenesis of PFA, patients are first sensitized towards a
pollen allergen, such as Bet v 1 (Bet), a birch pollen allergen
belonging to the pathogenesis-related (PR)-10 protein
family.12,13 PR-10 proteins share a high degree of
amino acid sequence identity as well as structural homology and
facilitate cross-reactivity of pollen-specific IgE antibodies and T
cells with food allergens, which initiates the development of secondary
food allergies.14–17 PR-10 proteins are found in
different plant pollen and in edible plant parts like hazelnut (Cor a 1,
Cor), apple (Mal d 1) and carrot (Dau c 1).7,18Interestingly, the hazelnut allergen isoform Cor a 1.04 is more similiar
to the birch pollen isoallergen Bet v 1.0101 than to the hazel pollen
isoallergen Cor a 1.01.19
In contrast to the ongoing spread of allergic diseases due to
cross-reactivities, the selection of efficient and long-lasting
therapies that improve pollen and cross-reactive food allergies together
are sparse. The only disease-modifying therapy available is
allergen-specific immunotherapy (AIT), which might achieve a 20-50%
reduction of combined symptom and medication
scores.20–22 But several years of therapy are needed
to maintain the therapeutic success23,24 and
placebo-controlled studies showed that pollen AIT have little to no
clinical effect on the associated food allergy.25–28Therefore, the current state of the art regarding treatment of PFA
remains unsatisfying and novel therapeutic strategies have to be
explored.
Autologous tolerogenic dendritic cells (tolDC) are promising candidates
for cell-based immunomodulatory therapies, as they can be differentiated
from peripheral blood cells of patients ex vivo based on
standardized protocols.29–31 After loading with the
desired antigen, they are reintroduced into the patients, where they are
generally well tolerated without any severe side
effects.32–34 In our group, we found that Interleukin
(IL) 10-modulated DC (IL-10 DC) are exceptionally suited for
tolerance-inducing therapies, as they displayed a stable, tolerogenic
phenotype, with strong migratory and suppressive
functions.30,35–37 Induced Treg (iTreg) primed by
these IL-10 DC exhibited a suppressive phenotype resulting in highly
efficient antigen-specific regulatory functions.38,39In this study, we combined our expertise in IL-10 DC and iTreg biology
demonstrating the capacity of IL-10 DC as inducers of iTreg which
facilitated allergen-specific and cross-reactive tolerance in birch
pollen allergic patients with associated hazelnut allergy in
vitro and in a humanized mouse model of allergy in vivo .