Differences in phenotype, homing properties and suppressive activities of regulatory T cells induced by epicutaneous, oral or sublingual immunotherapy in mice sensitized to peanut

Abstract

Allergen-specific immunotherapy has been proposed as an attractive strategy to actively treat food allergy using the following three different immunotherapy routes: oral (OIT), sublingual (SLIT) and epicutaneous (EPIT) immunotherapy. Regulatory T cells (Tregs) have been shown to have a pivotal role in the mechanisms of immunotherapy. The aim of this study was to compare the phenotype and function of Tregs induced in peanut-sensitized BALB/c mice using these three routes of treatment. We show that although EPIT, OIT and SLIT were all able to effectively desensitize peanutsensitized mice, they induced different subsets of Tregs. Foxp3+ Tregs were induced by the three treatment routes but with greater numbers induced by EPIT. EPIT and OIT also increased the level of LAP+ Tregs, whereas SLIT induced IL-10+ cells. The suppressive activity of EPIT-induced Tregs did not depend on IL-10 but required CTLA-4, whereas OIT acted through both mechanisms and SLIT was strictly dependent on IL-10. Moreover, the three routes influenced the homing properties of induced Tregs differently, with a larger repertoire of chemokine receptors expressed by EPIT-induced Tregs compared with OIT-and SLIT-induced cells, resulting in different protective consequences against allergen exposure. Furthermore, whereas OIT-or SLIT-induced Tregs lost their suppressive activities after treatment was discontinued, the suppressive activities of EPIT-induced Tregs were still effective 8 weeks after the end of treatment, suggesting the induction of a more long-lasting tolerance. In summary, EPIT, OIT and SLIT mediated desensitization through the induction of different subsets of Tregs, leading to important differences in the subsequent protection against allergen exposure and the possible induction of tolerance.

Animal models of allergen‐specific immunotherapy in food allergy: Overview and opportunities

“…The concept of oral tolerance has been studied in rodents since 1910, with early studies describing how oral ingestion of antigen would inhibit later experimental hyperactivity, thus demonstrating that tolerance to ingested food involves active antigen-specific suppression of hypersensitivity. Oral IT (OIT) models have been developed using egg white, 12 ovomucoid (native or heated), 12 ovalbumin, 13 cow's milk proteins (CMPs) 14, 15 and peanut [15][16][17] in sensitized mice. [10,11]).…”

“…14 Unexpectedly, IT in ovalbumin-sensitized mice did not result in the generation of CD4 + CD25 + FoxP3 + regulatory T cells, 13 and ex vivo allergen-specific IL-10 was suppressed in mice receiving OIT. The study using peanut IT 16 found, that the expansion of regulatory T cells was abrogated 8 weeks posttherapy, and the induced regulatory T cells were unable to transfer desensitization to sensitized mice. The study using peanut IT 16 found, that the expansion of regulatory T cells was abrogated 8 weeks posttherapy, and the induced regulatory T cells were unable to transfer desensitization to sensitized mice.…”

The Skin as a Route of Allergen Exposure: Part II. Allergens and Role of the Microbiome and Environmental Exposures

“…In milk-sensitized mice, EPIT was shown to induce milk-specific Treg cells that subsequently promoted tolerance to cutaneously administered peanut and house dust mite [79]. Similar to respiratory and sublingual routes of allergen exposure, where allergen tolerance is attributed to the induction of Treg cells and IL-10 [80], epicutaneous tolerization to antigen is likely to involve Treg-like cells [81]. Based on the localization of LCs below the stratum corneum and TJ within the stratum granulosum, it was largely believed that LCs could only be activated by antigens small enough (<500 Da) to surpass the stratum corneum (SC)/TJ barrier or else after disruption of the SC/TJ skin barrier integrity [82].…”

Experimental Models for Studying Food Allergy

“…The allergen is taken up by dermal dendritic cells and Langerhans cells, processed, and presented to T cells in the lymph nodes to elicit an immune response 10 . Repeated application of the allergen has been demonstrated to decrease reactivity to the allergen and to increase effector memory and naive regulatory T cells (Tregs) in the spleen 11 . Tregs induced from EPIT maintain their suppressive properties for a longer period after the end of the treatment than those generated from OIT.…”

“…Tregs induced from EPIT maintain their suppressive properties for a longer period after the end of the treatment than those generated from OIT. This may be because although both routes of immunotherapy promote effector memory Tregs, EPIT also promotes induction of naive Tregs that are more capable of proliferating and surviving than effector cells 11 . In patients with peanut allergies, 1 year of daily EPIT with 250 μg peanut protein applied by using Viaskin increased the dose needed to elicit an allergic response by at least 10-fold from their baseline tolerable dose 12 .…”