Sublingual allergen-specific immunotherapy (SLIT) intervention improves the control of grass pollen allergy by maintaining allergen tolerance after cessation. Despite its widespread use, little is known about systemic effects and kinetics associated to SLIT, as well as the influence of the patient sensitization phenotype (Mono- or Poli-sensitized). In this quest, omics sciences could help to gain new insights to understand SLIT effects.

47 grass-pollen-allergic patients were enrolled in a double-blind, placebo-controlled, multicenter trial using GRAZAX® during 2 years. Immunological assays (sIgE, sIgG4 and ISAC) were carried out to 31 patients who finished the trial. Additionally, serum and PBMCs samples were analyzed by metabolomics and transcriptomics, respectively. Based on their sensitization level, 22 patients were allocated in Mono or Poli-sensitized groups, excluding patients allergic to epithelia. Individuals were compared based on their treatment (Active/Placebo) and sensitization level (Mono/Poli).

Kinetics of serological changes agreed with those previously described. At two years of SLIT, there are scarce systemic changes that could be associated to improvement in systemic inflammation. Poli-sensitized patients presented a higher inflammation at inclusion, while Mono-sensitized patients presented a reduced activity of mast cells and phagocytes as an effect of the treatment.

The most relevant systemic change detected after two years of SLIT was the desensitization of effector cells, which was only detected in Mono-sensitized patients. This change may be related to the clinical improvement, as previously reported, and, together with the other results, may explain why clinical effect is lost if SLIT is discontinued at this point.

Component resolved diagnosis can be very valuable for the diagnosis and treatment of honeybee venom allergy (HVA) patients. Our aim is to study whether any of the allergens not included in the usual diagnostic platforms are relevant in our population.

The allergenic sensitization profile of Spanish patients who suffered a systemic reaction after a honeybee sting and were diagnosed with HVA was studied by immunoblotting using raw autochthonous Apis mellifera venom obtained and characterized by SDS-PAGE and mass spectrometry and with a commercial assay (ImmunoCAP).

Allergens described in the International Union of Immunological Societies (IUIS) database were detected in the A. mellifera raw venom extract used, except Api m 12. Sera from 51 patients with a median age of 46.2 years (interquartile range 35.6-54.6) were analyzed. Api m 1 and Api m 10 were detected as major allergens (88.2% and 74.5% respectively) using ImmunoCAP. Moreover, Api m 6 (85.4%) was found by immunoblotting.

Api m 1, Api m 6 and Api m 10 are major A. mellifera venom allergens recognized in our population.

Allergen immunotherapy is currently the only causal treatment for allergic diseases in human beings and animals. It aims to re-direct the immune system into a tolerogenic or desensitized state. Requirements include clinical efficacy, safety, and schedules optimizing patient or owner compliance. To achieve these goals, specific allergens can be formulated with adjuvants that prolong tissue deposition and support uptake by antigen presenting cells, and/or provide a beneficial immunomodulatory action. Here, we depict adjuvant formulations being investigated for human and veterinary allergen immunotherapy.

Venom immunotherapy (VIT) is highly effective and the treatment of choice for patients with a history of systemic anaphylactic reactions to a Hymenoptera sting. It has been assumed that VIT protocols with a rapid dose increase during the induction phase are associated with a higher frequency of systemic reactions (SR); however, study data addressing this issue are conflicting.

The aim of this study was to compare the safety of 3 different Hymenoptera VIT protocols (half-day ultra-rush, 3-day rush, 3-week cluster).

This retrospective 2-center study included 143 Hymenoptera venom-allergic patients, who underwent 147 VIT procedures during the years 2015-2018. Twenty cluster, 75 rush, and 52 ultra-rush VIT protocols were performed with honeybee (54 protocols) and wasp (93 protocols) venom. All documented side effects were classified into large local and SR (Ring and Messmer classification).

SR were observed during 11 (7.5%) VIT procedures and did not exceed severity grade II. SR occurred more frequently in cluster compared to accelerated protocols. This result was observed for both honeybee (cluster: 25%, rush: 8.7%, and ultra-rush: 15.8%) and wasp VIT (cluster: 12.5%, rush: 0%, and ultra-rush: 6.1%), though the differences were statistically significant only in the wasp VIT subgroup. Honeybee venom elicited more SR than wasp venom (14.8 and 3.2%, respectively, p = 0.01). The risk for SR did not depend on age, sex, concomitant antihypertensive medication, hypertryptasemia, or severity of the index sting reaction.

Accelerated VIT protocols, namely, rush and ultra-rush protocols are safe therapeutic options for Hymenoptera venom-allergic patients and displayed fewer SR than cluster VIT protocols in our study.

Food allergy quality of life (FAQL) is impaired in children with peanut allergy. Food Allergy Quality of Life Questionnaires (FAQLQs) provide disease-specific insight into the burden of peanut allergy and potential FAQL changes following peanut immunotherapy.

To examine FAQL changes in children following treatment with epicutaneous immunotherapy (EPIT) for peanut allergy (250μg, daily epicutaneous peanut protein; DBV712 250μg).

FAQL was prospectively measured using the FAQLQ parent proxy form (FAQLQ-PF, for children aged ≤12 years) and child form (FAQLQ-CF, child rated if aged ≥8 years) during the 12-month double-blind, randomized, controlled PEPITES trial and the initial 12 months of the open-label PEOPLE follow-up study. Data were analyzed for between-group differences after treatment unblinding.

FAQLQ from placebo participants (-PF: 96; -CF: 47) and treatment group participants (-PF: 209; -CF: 105) were analyzed. Twenty-four-month global FAQL scores (FAQLQ-PF/CF) were significantly improved in the treatment versus placebo group (least squares [LS] mean 0.34, P=0.008 and 0.46, P=0.023, respectively). At 24 months, there was significant FAQLQ-PF score improvement in participants initially randomized to treatment who met the efficacy primary endpoint (n=74, LS mean 0.55, P<0.001) and in participants with any eliciting dose increase (n=127, LS mean 0.66, P<0.001). FAQLQ-PF improvements were observed in social dietary limitations (P=0.002), food-related anxiety (P=0.029), and emotional impact (P=0.048) domains. FAQLQ-CF improvements were observed in risk of accidental exposure (P=0.002) and allergen avoidance (P=0.04) domains. Nearly all outcomes met a non-treatment context MCID previously cited for FAQLQ.

EPIT treatment was observed to be associated with significant global and domain-specific FAQL improvement (FAQLQ-PF/-CF), largely driven by increases in eliciting dose, in children with peanut allergy.

Allergic diseases have been a global problem over the past few decades. The effect of allergic diseases on healthcare systems and society is generally remarkable and is considered as one of the most common causes of chronic and hospitalized disease. The functional ability of probiotics to modulate the innate/acquired immune system leads to the initiation of mucosal/systemic immune responses. Gut microbiota plays a beneficial role in food digestion, development of the immune system, control/growth of the intestinal epithelial cells and their differentiation. Prescribing probiotics causes a significant change in the intestinal microflora and modulates cytokine secretion, including networks of genes, TLRs, signaling molecules and increased intestinal IgA responses. The modulation of the Th1/Th2 balance is done by probiotics, which suppress Th2 responses with shifts to Th1 and thereby prevent allergies. In general, probiotics are associated with a decrease in inflammation by increasing butyrate production and induction of tolerance with an increase in the ratio of cytokines such as IL-4, IL-10/IFN-γ, Treg/TGF-β, reducing serum eosinophil levels and the expression of metalloproteinase-9 which contribute to the improvement of the allergic disease’s symptoms. Finally, it can be said that the therapeutic approach to immunotherapy and the reduction of the risk of side effects in the treatment of allergic diseases is the first priority of treatment and the final approach that completes the first priority in maintaining the condition and sustainability of the tolerance along with the recovery of the individual.

Oral immunotherapy (OIT) is effective in desensitizing food-allergic patients but adverse events limit its applicability.

To identify risk factors for home epinephrine-treated reactions during the build-up phase of OIT.

A retrospective cohort study of patients older than 3.7 years undergoing OIT for food allergy at Shamir Medical Center between April 2010 and March 2019. All patients with a final disposition of full desensitization, partial desensitization, or failure were analyzed. Risk factors and outcome of home epinephrine-treated reactions were examined.

A total of 1037 patients (mean age, 8.4 years) who underwent 1100 OIT treatments (milk, n = 710; peanut, n = 213; egg, n = 50; sesame, n = 57; and tree nuts, n = 70) reached a final disposition and were analyzed. Full desensitization was achieved in 763 (69.4%) treatments, partial desensitization in 219 (19.9%), and 118 (10.7%) failed. Epinephrine was administered to 121 patients (11.7%) during 10.8% of treatments. Milk OIT was a significant risk factor both for epinephrine-treated reactions (odds ratio, 2.15; 95% CI, 1.25-3.68) and for low rate of full desensitization following such reactions compared with nonmilk OIT (18.2% vs 73.9%, respectively; P < .0001). Risk factors during milk OIT included asthma, pre-OIT reaction severity, lower tolerated dose, and epinephrine-treated reactions during clinic updosing, whereas risk factors during nonmilk OIT were male sex and lower tolerated dose.

Milk OIT poses a significant risk for home epinephrine-treated reactions during OIT and for poor outcome following such reactions. Together with the additional risk factors described for both milk and nonmilk OIT, this information may assist in patient selection for treatment.

Oral immunotherapy (OIT) can successfully desensitize allergic individuals to offending foods such as peanut. Our recent clinical trial (NCT02103270 ) of peanut OIT allowed us to monitor peanut-specific CD4+ T cells, using MHC-peptide Dextramers, over the course of OIT. We used a single-cell targeted RNAseq assay to analyze these cells at 0, 12, 24, 52, and 104 weeks of OIT. We found a transient increase in TGFβ-producing cells at 52 weeks in those with successful desensitization, which lasted until 117 weeks. We also performed clustering and identified 5 major clusters of Dextramer+ cells, which we tracked over time. One of these clusters appeared to be anergic, while another was consistent with recently described TFH13 cells. The other 3 clusters appeared to be Th2 cells by their coordinated production of IL-4 and IL-13, but they varied in their expression of STAT signaling proteins and other markers. A cluster with high expression of STAT family members also showed a possible transient increase at week 24 in those with successful desensitization. Single cell TCRαβ repertoire sequences were too diverse to track clones over time. Together with increased TGFβ production, these changes may be mechanistic predictors of successful OIT that should be further investigated.

Artemisia annua is an important autumnal pollen allergen for seasonal allergic rhinitis (SAR) in northern China. To date, no study has investigated allergen immunotherapy with A annua. We aimed to investigate the efficacy and mechanisms underlying A annua‐sublingual immunotherapy (SLIT).

This was a randomized, double‐blind, placebo‐controlled phase III clinical trial involving 71 SAR patients, randomized to SLIT with A annua extract (n = 47) or placebo (n = 24) for 32 weeks. Total nasal symptom score (TNSS; primary clinical end point) was evaluated at baseline (peak pollen phase (PPP) in the previous year), initiation of A annua‐SLIT, 1st PPP during SLIT, end of SLIT and 2nd PPP during follow‐up. Blood samples and nasal secretions were collected at beginning and after SLIT for assessment of T cells and inflammatory mediators. Safety was assessed according to adverse events (AEs) reported.

Artemisia annua‐SLIT significantly reduced TNSS to a greater level from baseline (from 9.45 ± 1.68 to 6.16 ± 2.27) than placebo (from 9.29 ± 2.09 to 9.05 ± 2.40) at the 1st PPP (P < .001) and sustained the improvement in symptoms throughout to the 2nd PPP. Preseasonal A annua‐SLIT for 16 weeks significantly decreased Th2 cells, increased nTreg and Tr1 cells in blood; and increased cystatin 1 (CST1) in nasal secretion after 16 and 32 weeks compared with pretreatment. Overall, 17/47 patients experienced mild local AEs and 2 patients mild systemic AEs, after A annua‐SLIT.

Artemisia annua‐SLIT is an efficacious and safe treatment in patients with A annua SAR.

In the last twenty years, several studies have been conducted in the search for new therapeutic strategies in patients with food allergy; in particular, after the failure of injection immunotherapy, three different routes of administration, oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT), have been teste. The aim of this manuscript is to review OIT, SLIT and EPIT clinical trials on food allergies and to suggest advantages an limits of the different routes of immunotherapy administration.

Of the three different routes of immunotherapy used in the treatment of food allergy, OIT is, at present, the only one actually able to induce an increase in tolerance in the majority of patients. However, its use is affected by serious secondary effects, such as major abdominal symptoms and anaphylaxis. The combination with omalizumab reduces the percentage of serious side effects. There are not many studies with SLIT for food allergy, but they have nevertheless shown that it is possible to obtain an increase in tolerance; however, this increase is modest in comparison with that obtained by OIT. EPIT, performed through the diffusion of allergens on intact skin, is the most recent form of immunotherapy. Although there are many works on EPIT carried out in laboratory animals, only few clinical studies have been published in humans. EPIT, unlike OIT and SLIT, is not responsible for systemic secondary effects such as anaphylaxis and eosinophilic oesophagitis but only for local an mild effects in areas where the devices are applied. Moreover, EPIT is characterized by high patient adherence.

OIT seems to have a prevalent application in patients who do not report previous symptoms of systemic or gastroenteric anaphylaxis, while SLIT and EPIT, in particular, could be more preferentially used in patients with a risk of anaphylaxis.