Journal of Allergy and Clinical Immunology最新文献

Background: Therapies targeting interleukin-5 (IL-5) or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma.

Objective: To investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors.

Methods: Surface IL-5Rα expression was investigated on MCs and their progenitors in mouse lungs and bone marrow, and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma, before and after anti-IL-5 (mepolizumab) or anti-IL-5Rα (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Rα therapy.

Results: Approximately 50% of the human primary lung MCs, and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Rα. In patients with mild-to-moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Rα ⁺ MC progenitors was elevated. Additionally, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Further, patients with severe asthma from two independent cohorts demonstrated a reduction of blood MC progenitors after anti-IL-5 or anti-IL-5Rα treatment. This was associated with improved asthma control, as well as a decline in both blood eosinophils and Th2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Rα (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation.

Conclusion: This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Rα in severe asthma also may involve reduction of MC populations.

Food Protein-Induced Enterocolitis (FPIES) is a non-IgE mediated GI food allergy characterized by delayed, protracted vomiting, accompanied by lethargy and pallor, usually 1-4 hours following ingestion of the food allergen. The pathophysiology of FPIES remains unknown and currently there are no diagnostic biomarkers available to assess disease activity or its resolution. Over the last two decades, FPIES has become increasingly recognized in both pediatric and adult patients. Forty years later after the initial FPIES description, the first international classification of diseases (ICD-10) code for FPIES was established and the first international consensus guidelines for diagnosis and management of FPIES was published. On June 22, 2022, the National Institute of Allergy and Infectious Diseases (NIAID) held its first virtual multidisciplinary workshop on FPIES. Various clinical and translational aspects of FPIES, as well as the important areas of unmet needs were discussed as priorities for future research during this 2-day virtual workshop. The following report provides a summary of content of the workshop, including updated literature on the topic areas, as well as providing a critical commentary on the state of FPIES.

Initiation of newborn screening (NBS) programs in Europe dates back to the 1960s. One of the most recent expansions of NBS programs was the addition of severe combined immunodeficiency (SCID) based on detection of T-cell receptor excision circles (TRECs). In this review, we present an overview of the current situation in Europe. To avoid a biased overview based on only published results, a 37-item survey on TREC-based NBS was sent to representatives of 46 European countries. With a response rate of 83%, we collected data of 38 countries. Seventeen of the 38 European countries that have completed the survey have nationally or regionally implemented TREC-based NBS. The survey results emphasize similarities and differences as well as common practices and challenges in TREC-based NBS. Because TRECs are a general surrogate marker for severe T lymphocytopenia, conditions other than SCID are also identified. Therefore, the initial definition of the target disease as "SCID" might need to be reconsidered and extended to "SCID and severe T lymphocytopenia." Even though complete harmonization of TREC-based NBS programs across Europe will remain challenging, collaboration and close partnerships will help in the move toward universal TREC-based screening for all newborns, resulting in more infants with SCID and severe T lymphocytopenia being detected each year.

Background: Results from the POISED trial suggest that discontinuation of peanut oral immunotherapy can increase the risk of regaining clinical reactivity to peanut.

Objective: We sought to determine whether those who achieved sustained unresponsiveness (SU) or sustained high threshold (SHT) have different baseline sequential epitope-specific (es-) IgE profiles than those who achieved transient desensitization (TD).

Methods: Subjects in the POISED trial (NCT02103270) were randomized to peanut (n=95) or placebo (n=25) for 24 months. OIT-desensitized subjects were then assigned to no peanut (PN-0, n=51) or 300mg (PN-300, n=30) for 12 months. SU and SHT were determined by those in PN-0 and PN-300, respectively, passing 4000mg peanut oral challenge. Specific IgE and IgG4 levels to peanut, Ara h 1-3 proteins and 64 allergenic epitopes were measured. We developed machine learning glmnet models with bootstrap simulations using baseline data to predict SU/SHT.

Results: Eighty (84%) subjects were desensitized to peanut. Of those, 13% (n=8) and 37% (n=13) achieved SU/SHT in PN-0 and PN-300. Decreases in epitope-and protein-specific IgE levels and increases in IgG4 levels were observed during 2 years of OIT. At baseline, patients with SU in Peanut-0 but not Peanut-300 had lower es-IgE and protein-sIgE levels compared to the TD group. A machine-learning model with 12 baseline es-IgEs and age could predict SU/SHT with an accuracy of 94%, AUC 0.97, Sensitivity 1.00, Specificity 0.91.

Conclusions: Patients who achieved SU/SHT have different baseline protein-and epitope-specific IgE profiles than those with TD. These profiles may help identify patients with an increased likelihood of achieving SU/SHT.

Background: CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19+ receptors on B-cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.

Objective: To evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.

Methods: We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (immunoglobulin G [IgG]≤600mg/dL), infections pre- and post-CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.

Results: Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy (587 to 362 mg/dL; p<0.0001). 37% of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was associated with worsening hypogammaglobulinemia post-CAR-T therapy. Hypogammaglobulinemia post-CAR-T therapy was associated with an increased risk of serious infection post-CAR-T therapy (IRR=2.7; 95% CI=1.5-5.2; p=0.002). Risk factors for mortality included mild hypogammaglobulinemia (400mg/dL

Conclusions: We identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia post-CAR-T therapy, which was associated with an increased risk of serious infection and mortality post-CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.

Food allergy is a growing problem that can have a significant impact on both the individual, the family, and society. We are entering a new era of food allergy management with the recent US Food and Drug Administration approvals of 2 therapies for food allergy. IgE is now known to play a critical role in allergic diseases, including food allergy. Ant-IgE therapy has been under investigation for decades and is now approved for asthma, urticaria, nasal polyps, and most recently, IgE-mediated food allergy. Here, we evaluate what is known about the safety and efficacy of anti-IgE therapy as monotherapy and in combination with oral immunotherapy. In addition, we will highlight important practical considerations and key knowledge gaps.