Efficacy and Safety of Dupilumab in Children With Peanut Allergy: A Multicenter, Open-Label, Phase II Study.

Background: Peanut allergy is a potentially life-threatening food allergy in children. This study explored whether dupilumab, a human monoclonal immunoglobulin (Ig)G4 antibody that blocks the activity of interleukin (IL)-4/IL-13, improved safety and desensitization to peanut exposure in children with peanut allergy.

Methods: A Phase II, 24-week, multicenter, single-arm, open-label, proof-of-concept study was conducted in the USA and Canada (NCT03793608).

Dupilumab as an Adjunct to Oral Immunotherapy in Pediatric Patients With Peanut Allergy.

Background: Peanut allergy is a common, life-threatening food allergy in children. We evaluated whether dupilumab, which blocks the activity of interleukin (IL)-4/IL-13, enhances the efficacy of oral immunotherapy (OIT) AR101 in pediatric patients with peanut allergy.

Methods: A Phase II, multicenter, randomized, double-blind study was conducted in the USA (NCT03682770) in pediatric patients (6-≤ 17 years old) with confirmed peanut allergy.

Phase 1 trial supports safety and mechanism of action of peptide immunotherapy for peanut allergy.

Background: Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution.

T cells specific to multiple Bet v 1 peptides are highly cross-reactive toward the corresponding peptides from the homologous group of tree pollens.

Background: Allergens from Fagales trees frequently cause spring allergy in Europe, North America, and some parts of Asia. The definition of the birch homologous group, which includes birch (Bet v), oak (Que a), alder (Aln g), hazel (Cor a), hornbeam (Car b), beech (Fag s), and chestnut (Cas s), is based on high allergen sequence identity and extensive IgE cross-reactivity. Clinical effect was seen during the alder/hazel, birch, and oak pollen seasons after treatment with tree SLIT-tablets containing only birch allergen extract.

Safety and immunopharmacology of ASP0892 in adults or adolescents with peanut allergy: two randomized trials.

Background: New treatment options with improved safety and novel mechanisms of actions are needed for patients with peanut allergy.

Objectives: To evaluate the safety, tolerability, and immunogenicity of ASP0892, a peanut DNA vaccine, after intradermal (id) or intramuscular (im) administration in adult or adolescent patients with peanut allergy in two phase 1 studies.

Methods: ASP0892 or placebo was administered every 2 weeks for a total of 4 doses.

Mechanisms and Predictive Biomarkers of Allergen Immunotherapy in the Clinic.

Allergen immunotherapy (AIT) remains to be the only disease-modifying treatment for IgE-mediated allergic diseases such as allergic rhinitis. It can provide long-term clinical benefits when given for 3 years or longer. Mechanisms of immune tolerance induction by AIT are underscored by the modulation of several compartments within the immune system.

Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy.

Background: Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions.

Objective: This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT).

Methods: We first performed ex vivo T-cell profiling on peanut-reactive CD154CD137 T (pTeff) cells from 90 challenge-confirmed PA individuals.

Clinical and immunological evaluation of cat-allergic asthmatics living with or without a cat.

Background: Characterising the clinical and immunological impact of daily cat exposure in cat-allergic subjects with asthma who live with cats (WC) and those who do not (WoC) may provide understanding of the drivers of the allergic response.

Methods: Clinical and immunological characteristics (skin prick test, spirometry, symptom assessments, immunological markers) were compared between asthmatic subjects WC (n = 10) and WoC (n = 9).

Results: WC subjects had greater use of long-acting beta agonists (p < .

Optimal human pathogenic T2 cell effector function requires local epithelial cytokine signaling.

Background: IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity [ST2]) is a differentially expressed gene in pathogenic T2 cells, but its role in T-cell effector function has not been elucidated.

Objective: We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses.

The Use of pMHCII Tetramer Technology for the Identification and Characterization of CD4+ T Cells.

Understanding the mechanism underlying allergic disease is dependent upon definition of the heterogeneity and complexity of the cellular immune response toward allergens both in the context of disease and clinical intervention. Among all components of the immune system, CD4+ T cells play a key role in the orchestration of immune response toward allergen and have become a dynamic area of research. Because of their unique ability to identify antigen-specific CD4+ T cells irrespective of functional outputs, fluorescently labeled peptide-MHC class II (pMHCII) tetramers in combination with multiparameter flow cytometry have now provided an unprecedented opportunity to track and subsequently quantify and characterize rare allergen-specific CD4+ T cells at single-cell level.

Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers.

Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung, and colon cancer.

Immune mechanisms of oral immunotherapy.

Oral immunotherapy (OIT) has demonstrated reproducibly successful desensitization in patients with food allergy completing clinical trials and, in some studies, sustained unresponsiveness. These clinical outcomes have been associated with characteristic modifications in the allergen-specific immune response, but a detailed synthesis of OIT's mechanisms of action is lacking. In this rostrum we review the current evidence regarding the human immune response to OIT, explore possible mechanisms, and identify knowledge gaps for future research.

Oral Tolerance Development and Maintenance.

The gastrointestinal tract has an abundant mucosal immune system to develop and maintain oral tolerance. The oral route of administration takes advantage of the unique set of immune cells and pathways involved in the induction of oral tolerance. Food allergy results from a loss of oral tolerance toward ingested antigens.

Synchronous immune alterations mirror clinical response during allergen immunotherapy.

Background: Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation.

Objective: We sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation.

A phenotypically and functionally distinct human T2 cell subpopulation is associated with allergic disorders.

Allergen-specific type 2 helper T (T2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic T2 cell types. We have described a subset of human memory T2 cells confined to atopic individuals that includes all allergen-specific T2 cells.

Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4 T Cells in Peripheral Blood of Subjects with Type 1 Diabetes.

The significance of islet Ag-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior Ag exposure, inferred from expanded TCR clonotypes, and essential phenotypic properties in their transcriptomes. To test this, we developed single-cell RNA sequencing procedures for identifying TCR clonotypes and transcript phenotypes in individual T cells.

Human Immune Monitoring Techniques during Food Allergen Immunotherapy.

Purpose Of Review: Encouraging results from recent food allergen immunotherapy clinical trials indicate that the immune system plays an essential role in peripheral tolerance to food allergen. Thus, the monitoring of changes in immune responses and their possible correlation with clinical outcome in allergic patients receiving immunotherapies could theoretically serve as surrogate markers and be harnessed as rationale for food allergen immunotherapy development.

Recent Findings: A shift towards antigen specificity in recent assays has provided a solid foundation for the elucidation of cellular mechanisms involved in food allergen immunotherapy as well as the tracking of allergen-specific immune cells.

Lack of allergy to timothy grass pollen is not a passive phenomenon but associated with the allergen-specific modulation of immune reactivity.

Background: Timothy grass (TG) pollen is a common seasonal airborne allergen associated with symptoms ranging from mild rhinitis to severe asthma.

Objective: The aim of this study was to characterize changes in TG-specific T cell responses as a function of seasonality.

Methods: Peripheral blood mononuclear cells (PBMCs) obtained from allergic individuals and non-allergic controls, either during the pollen season or out of season, were stimulated with either TG extract or a pool of previously identified immunodominant antigenic regions.

Effect of allergen-specific immunotherapy on CD4+ T cells.

Purpose Of Review: The aims of this review are to discuss the impact of chronic high-dose allergen exposure on allergen-specific CD4(+) T-cell subset during allergen-specific immunotherapy (AIT) and discuss recent advances supporting novel mechanisms for desensitization and tolerance induction during AIT. (Figure is included in full-text article.)

Recent Findings: New technologies for direct molecular and cellular analysis have now provided an unprecedented opportunity to compare the functions and phenotypes of allergen-specific T cells at a single cell level, both in the context of disease and clinical intervention.

Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization.

Background: In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood.

Objective: We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced.

Biomarkers for antigen immunotherapy in allergy and type 1 diabetes.

Allergy and type 1 diabetes are immune mediated diseases that, despite being etiologically distinct, each have inappropriate activation and effector function of antigen-specific T cells in the pathogenic process. Understanding changes in the frequency and phenotype of these cells is critical to improve assessment of disease diagnosis and prognosis and effectively assess immunological response to therapy. In the setting of antigen-specific therapy in allergy and type 1 diabetes, assays to monitor the immunological mechanisms of disease have been improving in recent years, and we are getting closer to an accurate understanding of how the cellular immune response is modulated during treatment.