Regulation of IgE-mediated signalling in human basophils by CD32b and its role in Syk down-regulation: basic mechanisms in allergic disease. Clin Exp Allergy 2014;44:713-23. 7. Warmerdam PA, van de Winkel JG, Vlug A, Westerdaal NA, Capel PJ. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding.

RATIONALE: Allergen-specific immunotherapy aims to induce long term tolerance, possibly through the generation of regulatory T-cells (Tregs). This study analyzed the phenotype and suppressive activities of Tregs induced by EPIT, OIT or SLIT and their sustainability. METHODS: BALB/c mice were orally sensitized to peanut and treated by EPIT, SLIT, OIT or left untreated (Sham). The proportion and phenotype of CD4+CD25+Foxp3+ cells (Tregs) were analyzed by flow cytometry after 8 weeks of treatment or 8 weeks after termination. The suppressive activities of Tregs were evaluated by the decrease of peanut-specific responses after adoptive transfer into sensitized mice. RESULTS: Tregs increased at the end of 8-week EPIT, OIT and SLIT vs Sham, significantly more with EPIT. Tregs induced by EPIT, and less so by OIT, increased expression of CTLA-4. Only SLIT induced IL-10+ Tregs. EPIT-induced Tregs were both CD62L+ and CD62L-contrasting with mainly CD62L-with OITand SLIT. EPIT-induced Tregs expressed a larger repertoire of homing receptors compared to OIT and SLIT. Eight weeks after the discontinuation of EPIT, the level and phenotype of Tregs were maintained, but not after OITor SLIT. Peanut-specific responses in mice adoptively transferred with Tregs isolated at the end of EPIT, OIT or SLIT were decreased compared to mice not receiving transferred cells. However, when adoptive transfer was done with Tregs isolated 8 weeks after terminating treatment, only EPITinduced Tregs decreased peanut-specific responses. CONCLUSIONS: EPIT, OIT and SLIT induced Tregs with different phenotypes. Only EPIT-induced Tregs were maintained after discontinuation of treatment, suggesting induction of tolerance.

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The 12-month VIPES RCT of EPIT using ViaskinÒ Peanut (VP) was continued as an open-label trial for an additional 24 months. We report results of the 12-month interim analysis. METHODS: From 207 subjects completing the VIPES RCT (6-55 years), 171 (82.6%) entered the open-label extension. For this second year, 64.9% subjects initially treated with 50mg, 100mg, 250mg peanut protein (pp) i.e. VP50, VP100, VP250, or placebo were treated for 12 months with VP250. The remainder received VP50 or VP100 for 6 months before switching to VP250. Endpoint response was based on the proportion of successes, i.e. eliciting dose > _10-fold above baseline or > _1,000mg pp, at the 24-month DBPCFC. RESULTS: The response rates after 24 months EPITwith VP250 were 69.7% (23/33) overall and 80.0% (16/20) in children 6-11 years, compared to 50% overall and 53.6% in children after 12 months VP250 EPIT. Adolescents/ adults remained stable. In children, the peanut cumulative reactive dose after 24-months increased significantly compared to VIPES entry [mean(6SD)]: +1817.0(1853.9) mg pp; +983.3(1279.9) mg pp after 12-months. Children's median peanut-IgE decrease from baseline was-9% and-38% after 18 and 24 months; median peanut-IgG4 increase was +793.5% at 24 months. Mean(6SD) compliance was 94.8(611.0)%; there were no serious AEs related to VP. Interestingly, the 12-month VP250 treatment of the ex-placebo group exactly reproduced the significant response rate in VIPES study with 50.0% (23/46) overall, 53.6% (15/28) in children. CONCLUSIONS: The 24-month EPIT with VP250 is well accepted, safe and clearly enhances the 12-month therapeutic benefit overall and in children.

RATIONALE: To report long-term follow-up data describing frequency and quantity of home dosing of food allergens following desensitization with multi-OIT protocols as part of two previously published phase 1 clinical trials. METHODS: A total of 73 participants completed two single-center phase 1 trials evaluating the safety of OIT for multiple food allergens using a mOIT protocol (n543) or a rapid mOIT protocol with omalizimab (n530). In both trials, subjects were instructed to maintain daily dosing and if skin test for the allergen became negative, dosing was decreased. Participants returned yearly for follow-up food challenges. RESULTS: Long-term follow up data was available for 70 of 73 participants. The long-term follow-up period for participants who completed the mOIT protocol ranged from 18 to 73 months; 22 (56%) chose to consume 2g protein doses of each allergen, while 13 (33%) chose to consume between 300mg and 2g per allergen. In the rapid mOIT protocol, follow-up ranged from 11 to 46 months; 9 (30%) participants chose to consume 2g doses and 18 (60%) participants chose to consume doses between 300mg and 2g. All subjects in both groups remained desensitized to at least 2g protein of each of their food allergens on repeat food challenge, even those who chose to consume home doses as low as 300mg of their allergens three times per week. CONCLUSIONS: Subjects who completed a mOIT protocol continue to consume regular doses that maintain desensitization to 2g of each allergen.