To the editor,
The prevalence of cashew allergy has been rising in industrial
countries.1 More critically, accidental contact with
cashew-containing food is frequently associated with highly severe
anaphylactic reactions in allergic individuals.2 These
elements highlight the need for a safe treatment able to minimize the
impact of this life-threatening allergy.
In a recent study published in Allergy , our group evaluated the
relevance of investigational epicutaneous immunotherapy (EPIT) to
protect against anaphylaxis in a mouse model of cashew
allergy.3 We demonstrated that epicutaneous patches
containing cashew allergens were able to modulate cashew-specific
antibody responses and decrease cashew-specific Th2 responses in
cashew-sensitized animals. More importantly, EPIT was able to reduce
mast cell reactivity and to afford protection against anaphylactic
symptoms following oral challenge, suggesting that EPIT may be a safe
and efficacious approach to treat cashew allergy. During this work, we
demonstrated that epicutaneous patches were able to deliver cashew
allergen to skin dendritic cells (DC) using cashew protein extract
conjugated to Fluoroprobe-647 (cashew-F647). We showed a significant
increase of cashew-specific epidermal Langerhans cells, cDC1 and cDC2 in
the local draining lymph nodes of mice that received patches containing
cashew-F647 for 48 hours.
In the present work, we aimed to better characterize allergen capture at
the skin level while evaluating the capacity of cashew allergen to
modulate DC activation in sensitized or naïve animals. To that end,
epicutaneous patches containing cashew-F647 were applied to
cashew-sensitized or naïve mice for 6 hours (antibody titers measured
before patch application are depicted on Figure S1 ). Then, skin
was homogenized, and cells were analyzed by flow cytometry
(Figure 1 ). Langerhans cells and cDC2 were the two main subsets
of skin DC able to take up cashew allergen, in agreement with previously
published data.4 Remarkably, a significant increase of
cashew-positive Langerhans cells, cDC2 and cDC1 was observed in
sensitized mice compared to naïve animals. Note that the difference was
more pronounced for Langerhans cells, with a 47% increase of
allergen-positive cells among this subset. To further address the
activation status of these cashew-positive DC, the expression of CD86
and PD-L2 was measured in each skin DC subset (Figure 2 ). A
significant decrease in CD86 expression was measured for cashew-positive
Langerhans cells and cDC1 isolated in sensitized mice compared to naïve
mice. Conversely, a significant increase of PD-L2 expression was
observed in cashew-positive Langerhans cells and cDC2 isolated in
sensitized animals.
Previous data demonstrated that PD-L2 expression by skin DCs, especially
Langerhans cells and cDC2, is a key element leading to the generation of
Tregs and to the acquisition of tolerance to topically administered
allergen.4,5 Here, we demonstrated that the expression
of PD-L2 and CD86 on skin DC following topical allergen application
depends upon preexisting immunological status. Furthermore, these
results support the fact that a strong Th2 context promotes the
generation of tolerogenic skin DC characterized by a decrease in CD86
expression and an increase of PD-L2 expression, as previously shown by
our group using OVA as a model allergen.6
Further investigations are warranted to decipher the mechanisms by which
specific preexisting immunity impacts the capacity of skin DC to capture
topically administered allergens and to modify their activation status.
Our previous results suggest that preexisting IgG could efficiently
promote allergen uptake (unpublished data), but the mechanisms leading
to the modulation of CD86 and PD-L2 are still unknown.
Overall, these data provide additional insight into the mechanisms of
action of EPIT for cashew allergy treatment. They suggest that the
acquisition of tolerance to epicutaneous allergen would be more
efficient in highly sensitized individuals and that the underlying
mechanisms are embedded in the skin.