Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation

Suárez‐Fueyo, Abel; Ramos, Tania; Galán, Agustín; Jimeno, L; Würtzen, Peter Adler; Marín, Alicia; Frutos, C. De; Blanco, Carlos; Carrera, Ana C.; Barber, Domingo; Varona, Rosa

doi:10.1016/j.jaci.2013.09.043

Cited by 132 publications

(128 citation statements)

References 37 publications

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“…Studies of antigen-specific IT have implicated FOXP3-expressing Treg induction in association with immune tolerance in allergy, diabetes, and multiple sclerosis (7,(46)(47)(48)(49), and a subversion of Th2 or Th1 responses in allergy and diabetes, respectively (47,48,50). However, we observed a reduction in allergic Th2 cells and a reduction in antigen-specific regulatory cells in the peripheral blood over time during IT.…”

Section: Discussioncontrasting

confidence: 59%

Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets

Ryan

Hovde

Glanville

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.is a process in which small amounts of allergen are given over time to the allergic individual until they can safely tolerate high amounts of allergen with no signs of clinical symptoms (1-9). In the regimen of oral IT for peanut-allergic patients (identified by an allergic reaction during a standardized blinded food challenge to peanut), small amounts of peanut flour protein are ingested and escalated to a servings-worth of peanut protein (4 g of peanut protein) over a period of 2-3 y (6-7). Most patients require continuous frequent (e.g., daily) exposure to such therapy for beneficial clinical outcomes. Mechanistic studies of oral IT to food allergens, although limited to date, show that plasma markers such as IgE and IgG4 immunoglobulins, skin test markers, component testing, and basophil activation tests are only weakly predictive of long-term clinical success (10-16). T cells are critical upstream regulators of allergic sensitization that are required to help B cells to synthesize IgE/IgG4 immunoglobulins, which then can activate or inhibit basophils and mast cells (10-17). Moreover, successful IT is associated with the development of regulatory T cells (Tregs) that are thought to dampen allergic reactivity to offending allergens (7). We therefore focused on finding T-cell markers of immune tolerance that could be detected early in the peripheral blood during IT. CD4+ T cells can be relatively long-lived (compared with plasma proteins and basophils) and changes detected early in populations of T cells could perhaps predict longer-lasting successful IT. For example, in one of the first studies in peanut allergen IT to withdraw therapy for more than 10 wk, we previously showed that despite negative skin tests to peanut, and high IgG4/low specific IgE levels to peanut, and decreased basophil reactivity to the allergen, some patients who withdrew from therapy for 3-6 mo were still reactive upon rechallenge with peanut (7...

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Section: Discussioncontrasting

confidence: 59%

Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets

Ryan

Hovde

Glanville

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

124

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“…tolerance (28,29) and in the mechanism of AIT efficacy (12,30,31). However, specific Treg-based immunotherapies have not been evaluated in the context of food allergy.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Bonnet¹,

Vigneron

Levacher

et al. 2016

The Journal of Immunology

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“…It has been shown that AIT can induce the generation of anergy and/or deletion of allergen-specific T-cells, skewing allergen-specific responses from Th2 to a more protective Th1 phenotype, which downregulates IgEmediated immune response. Several studies have shown that AIT modifies the function of monocytes, B cells, and T cells, as well as basophils, eosinophils, and mast cells count [15][16][17][18]. At Case series or poor-quality cohort studies that fail to clearly define comparison C Favorable but no groups and/or fail to objectively measure exposures and outcomes (preferably conclusive blinded) and/or fail to identify or appropriately control known confounders and/or fail to ensure complete and sufficiently prolonged follow-up immune response to and clinical benefit from AIT [25].…”

Section: Main Immunological Changes Induced By Aitmentioning

confidence: 99%

“…The longitudinal analysis of humoral and cellular immune parameters in peripheral blood samples of patients receiving grass tablet SLIT revealed that changes in sIgE levels after therapy were linked to a specific (inhibitory) IgG4 response, and production of blocking antibodies correlated with TH2 response downregulation [18]. In fact, some evidence suggests that functional assays of inhibitory IgG4 and IgE-blocking factor may be more useful surrogates of clinical response than IgG4 levels [50].…”

Section: Biomarkers/predictor Of Responsementioning

confidence: 99%

Specific allergen immunotherapy for the treatment of allergic asthma: a review of current evidence

Domínguez‐Ortega

Delgado

Blanco

et al. 2017

J Investig Allergol Clin Immunol

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Asthma is frequently associated with atopy, characterized by the production of specific immunoglobulin E in response to environmental allergens. Currently, two types of allergen immunotherapy (AIT) are used in clinical practice: subcutaneous and sublingual immunotherapy, both accepted as key components of the therapeutic repertoire for allergic rhinitis and conjunctivitis. However, their role in asthma remains controversial. The present document is aimed at providing the clinicians with a review of the evidence on the use of AIT in asthma, focusing on the most relevant aspects of its mechanism of action, its efficacy, and existing data on safety, tolerability, and cost-effectivity, both in pediatric and adult populations. A systematic search of MEDLINE, Cochrane, and Clinical Trials databases from 2000 to April of 2016 was carried out by a panel of experts from the Spanish Allergy and Clinical Immunology Scientific Society. Relevant studies prior to the year 2000 included in ulterior systematic reviews were also considered. More than 4000 articles were identified during the search and 241 were selected to retrieve available evidence on AIT, which was graded according to the Oxford classification. All the group members reviewed the resulting text until the final version reached the consensual agreement. A summary of recommendations on the more relevant topics are proposed. The role of AIT as a valuable therapeutic strategy for prevention of exacerbation and progressive decline in lung function is highlighted. Future research should include specific tools for asthma evaluation when assessing AIT effectiveness in asthmatic patients. ResumenEl asma se asocia frecuentemente con alergia, entendida ésta como la producción de IgE específica frente a alérgenos ambientales. Actualmente, existen dos tipos de inmunoterapia específica con alérgenos (ITE) para la práctica clínica habitual: subcutánea y sublingual, ambas indicadas en el tratamiento de la rinitis y la conjuntivitis alérgicas. Sin embargo, su papel en el asma resulta todavía controvertido. Dominguez-Ortega J, et al.

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Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation

Cited by 132 publications

References 37 publications

Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets

Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Specific allergen immunotherapy for the treatment of allergic asthma: a review of current evidence

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