News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2018)

Tuft cells represent a rare population within the small intestine with an important role in defense against helminth infection through production of IL-25, which activates group 2 innate lymphoid cells (ILC2s) to initiate subsequent protective type 2 immune responses. Schneider et al (Cell 2018; https://doi.org/10.1016/j.cell.2018.05.014) have discovered that this pathway is activated by a protozoa-derived metabolite, which leads to small-intestine remodeling and enhanced antihelminth immunity. Mechanistically, fermentation of dietary fiber by the protozoa Tritrichomonas species in the small intestine led to accumulation of the metabolic end product succinate, which was then sensed by Tuft cells through the receptor GPR91 to activate the tuft cell–ILC2 circuit. Importantly, dietary succinate activated ILC2s in a tuft cell– and IL-25–dependent manner. The authors conclude that intestinal protozoa protect against helminth infection through host sensing of protozoa-derived succinate and subsequent activation of type 2 immunity. Image attribution. Used under Creative Commons CC BY 4.0 license. By users Roland Yao Wa Kouassi, et al [CC BY 4.0 (https://creativecommons.org/licenses/by/4.0)], via wikimedia commans.Intestinal protozoa protect against helminth infection through host sensing of protozoa-derived succinate Intestinal protozoa protect against helminth infection through host sensing of protozoa-derived succinate Dupilumab is an mAb directed against the α chain of the IL-4 receptor, which allows it to block signaling of both IL-4 and IL-13. Building on promising results in initial studies, 2 independent phase 3 randomized controlled trials have been conducted to test its efficacy in treating uncontrolled and glucocorticoid-dependent asthma. Castro et al (N Engl J Med 2018;378:2486-2496; https://doi.org/10.1056/NEJMoa1804092) randomized 1902 human subjects aged 12 years or older with uncontrolled asthma irrespective of baseline blood eosinophil counts or levels of biomarkers of type 2 inflammation to receive subcutaneous doses of either 200 or 300 mg of dupilumab or placebo every 2 weeks for 1 year. Compared with placebo, both doses of dupilumab statistically significantly decreased the annual severe asthma exacerbation rate by 47.7% and 46.0%, respectively. Additionally, both doses of dupilumab increased FEV1. Prespecified subgroup analysis identified that both doses of dupilumab decreased the exacerbation rate to a greater degree in patients with blood eosinophil counts of at least 300/mm3. In the second trial Rabe et al (N Engl J Med 2018;378:2475-85; https://doi.org/10.1056/NEJMoa1804093) randomized 210 patients with oral glucocorticoid–treated asthma to receive 300 mg of subcutaneous dupilumab or placebo every 2 weeks as an adjunct therapy for 24 weeks. Dupilumab decreased the required glucocorticoid dose by 70.1% compared with 41.9% with placebo (P < .001). Even though the glucocorticoid dose was decreased, dupilumab still reduced the severe exacerbation rate by 59% and improved FEV1. Collectively, these results demonstrate that dupilumab decreases exacerbations and increases lung function in patients with asthma, with a more pronounced effect in patients with increased blood eosinophil counts.Dupilumab decreases exacerbations and increases lung function in patients with asthma Dupilumab decreases exacerbations and increases lung function in patients with asthma Impaired barrier function of the esophageal epithelium is critical to pathogenesis of the emerging allergic disorder eosinophilic esophagitis (EoE), although the underlying molecular mechanisms remain incompletely understood. Azouz et al (Sci Transl Med 2018; https://doi.org/10.1126/scitranslmed.aap9736) identified an inhibitor of serine protease activity, serine peptidase inhibitor, Kazal type 7 (SPINK7), that acts as an important regulator of the homeostatic barrier function of the esophageal epithelium and exhibits decreased expression in patients with EoE. Loss of SPINK7 activity led to dysregulation of epithelial barrier function and differentiation; increased release of proallergic cytokines, including thymic stromal lymphopoietin (TSLP); and enhanced eosinophil activation through augmented activity of urokinase plasminogen-type activator. Importantly, the deleterious effects of SPINK7 silencing were reversed by exogenous administration of the antiprotease α1-antitrypsin. Finally, genetic epistasis was identified between TSLP and PLAU, which encodes urokinase plasminogen-type activator. Collectively, the authors have identified a critical role for a balance of the activity of SPINK7 and its target proteases in the pathogenesis of esophageal allergic inflammation and suggest that antiprotease replacement might be of therapeutic benefit. Image attribution. Used under Creative Commons CC BY 4.0 license. By user Nephron [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0). We asked first author Nurit Azouz, PhD, of Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, to comment on this study. She writes, “We learned from this study that esophageal epithelial cells not only provide a protective barrier from food antigens but also actively participate in immune responses by producing an arsenal of cytokines and chemokines and by activating eosinophils. We showed that the balance between proteases and their inhibitors is a key regulatory process in epithelial cell homeostasis and that downregulation of the protease inhibitor SPINK7 initiates massive inflammatory consequences. Treatment with the antiprotease α1-antitrypsin restored the phenotypes associated with SPINK7 loss. Therefore we suggest that delivery of antiproteases should be considered as a target for intervention in the treatment of allergic diseases, such as EoE.A critical role for a balance of the activity of SPINK7 and its target proteases A critical role for a balance of the activity of SPINK7 and its target proteases The success of neutralization of IL-5 by biologic therapies for the treatment of severe eosinophilic asthma has increased investigation into the therapeutic potential of targeting other type 2 cytokines, including IL-13. Three recent trials have been conducted to assess the efficacy of tralokinumab, an IL-13–neutralizing mAb, in the treatment of asthma. Russell et al performed a phase 2 randomized control trial (MESOS; Lancet Respir Med 2018; https://doi.org/10.1016/S2213-2600(18)30201-7) to assess the effect of tralokinumab on airway inflammation and remodeling. Seventy-nine human subjects with moderate-to-severe asthma were randomized to receive subcutaneous doses of 300 mg of tralokinumab or placebo every 2 weeks for 12 weeks. Although treatment with tralokinumab decreased fraction of exhaled nitric oxide (Feno) concentrations and total blood IgE levels, it did not affect eosinophil counts in the blood or sputum. Independently, Panettieri et al conducted 2 separate phase 3 randomized control trials (STRATOS 1 and 2; Lancet Respir Med 2018; https://doi.org/10.1016/S2213-2600(18)30184-X) to assess the efficacy of tralokinumab treatment. In STRATOS 1 1202 subjects with severe asthma were randomized to receive subcutaneous tralokinumab (300 mg) every 2 or 4 weeks or placebo every 4 weeks. Treatment with tralokinumab did not significantly reduce the overall annualized asthma exacerbation rate, but subgroup analysis revealed that tralokinumab did reduce the exacerbation rate in patients with a baseline Feno value of 37 parts per billion or greater by 44%. However, this finding was not replicated in the STRATOS 2 trial, in which 229 patients with high Feno values were randomized to receive the same dose of tralokinumab or placebo every 2 weeks. The findings of these studies support the idea that neutralization of IL-13 alone is not sufficient to prevent asthma exacerbation and suggest a requirement for concurrent neutralization of IL-4. Image attribution. Used under Creative Commons CC BY 2.0 license. By user Yale Rosen [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)], via wikimedia commans.Neutralization of IL-13 alone is not sufficient to prevent asthma exacerbationNews items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. Neutralization of IL-13 alone is not sufficient to prevent asthma exacerbation News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.