News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2017)

Benralizumab is a humanized mAb that depletes cells expressing the IL-5 receptor α subunit, including eosinophils, and reduces the frequency of asthma exacerbations. Nair et al (N Engl J Med 2017;376:2448-58; https://doi.org/10.1056/NEJMoa1703501) performed a randomized double-blind trial to determine the oral glucocorticoid–sparing potential of benralizumab in patients with severe asthma controlled with oral glucocorticoids in addition to inhaled corticosteroids and long-acting bronchodilators and evidence of an “eosinophil phenotype” demonstrated by blood eosinophilia. Two hundred twenty subjects received 30 mg of subcutaneous benralizumab every 4 weeks or every 8 weeks (after receiving the first doses every 4 weeks) or placebo every 4 weeks for 28 weeks. The 2 benralizumab groups significantly reduced the final oral glucocorticoid doses from baseline by 75% compared with a 25% reduction in the placebo group and yet had a 70% decreased rate of asthma exacerbations and improvement in asthma control while preserving FEV1. Importantly, there were no detectable differences in adverse events between the benralizumab treatment and placebo groups. Collectively, the authors find that benralizumab decreases the need for oral glucocorticoids to control severe asthma with associated eosinophilia.Benralizumab decreases the need for oral glucocorticoids Benralizumab decreases the need for oral glucocorticoids We asked author Dr Parameswaran Nair, MD, PhD, of McMaster University in Hamilton, Ontario, Canada, to comment on the study. He writes, “The treatment effect observed in this large study of patients with asthma severe enough to require daily oral prednisone and some evidence of eosinophils as potential effector cells is more impressive than previously demonstrated interventions. It remains to be seen whether this is due to depletion of eosinophils in airway tissue and lumen in addition to normalizing their levels in blood and whether there are any long-term consequences of this strategy.” Mast cells contribute to the pathogenesis of asthma and can resist steroid treatment. The development and survival of these cells requires activation of the receptor KIT. Imatinib, a 2-phenyl amino pyrimidine derivative, functions as a specific inhibitor of several tyrosine kinase enzymes, including KIT. Cahill et al (N Engl J Med 2017;376:1911-20; https://doi.org/10.1056/NEJMoa1613125) performed a randomized proof-of-concept study to determine whether inhibition of KIT with imatinib in patients with severe asthma decreases airway mast cell levels and airway hyperresponsiveness (AHR). Sixty-two patients with uncontrolled severe asthma received daily doses of imatinib or placebo for 24 weeks. Treatment with imatinib decreased AHR after 3 and 6 months of treatment compared with placebo. Imatinib treatment also decreased the number of mast cells in endobronchial biopsy specimens and serum levels of tryptase, which is released from activated mast cells. Adverse events associated with imatinib treatment included muscle cramps and low blood phosphate levels. These results show that treatment with imatinib decreased mast cell burden and AHR in patients with severe asthma. Further clinical studies should determine the efficacy of targeting mast cells in patients with severe asthma. Figure attribution: Used via Creative Commons license by user Jynto [CC0 1.0], via Wikimedia Commons.Decreased mast cell burden and AHR in patients with severe asthma Decreased mast cell burden and AHR in patients with severe asthma Type 2 cytokine–mediated activation of macrophages contributes to host defense from helminth infections, tissue repair, allergic responses, and fibrosis. The molecular mechanisms regulating macrophage activation in different tissues is not completely understood. Minutti et al (Science 2017;356:1076-80; https://doi.org/10.1126/science.aaj2067) examined in mice tissue-specific factors that regulate macrophage function during type 2 immunity. Genetic deletion of surfactant protein A (SP-A), the major protein component of surfactant, impaired type 2 immune responses and decreased both the proliferation and activation of alveolar macrophages in response to pulmonary helminth infection. Notably, SP-A treatment did not have the same effect in macrophages derived from the peritoneal cavity. Instead, peritoneal macrophages increased proliferation and activation in response to the structurally related complement protein C1q. Furthermore, C1q deficiency decreased peritoneal fibrosis and prevented optimal macrophage-mediated repair in response to liver bacterial infection. Importantly, IL-4 induced expression of SP-A in the lungs and C1q in the peritoneum and liver. Mechanistically, the activation of macrophages by SP-A or C1q occurred through the cell-surface receptor Myo18A, which itself is induced by IL-4. These collective results demonstrate that type 2 cytokines induce expression of tissue-specific local factors that regulate macrophage activation during type 2 immunity in mice.Type 2 cytokines induce expression of different local factors that regulate macrophage activation Type 2 cytokines induce expression of different local factors that regulate macrophage activation We asked authors Judith Allen, PhD, of the University of Manchester, Manchester, United Kingdom, and Cristina Casals, PhD, of Complutense University of Madrid, Madrid, Spain, about the study. They write, “The authors hope that the identification of tissue-specific pathways that amplify type 2 macrophage activation will allow for more targeted treatments to enhance wound repair or prevent fibrosis.” Type 2 immune responses involve clearance of foreign pathogens and subsequent resolution of inflammation and tissue repair. Bosurgi et al (Science 2017;356:1072-7; https://doi.org/10.1126/science.aai8132) identified an important role for detection of apoptotic cells in shifting type 2 immune responses toward resolution and repair. Concurrent exposure of apoptotic cells and IL-4 or IL-13, but not apoptotic cells alone or IL-4/IL-13 alone, to bone marrow-derived macrophages led to the expression of anti-inflammatory and tissue repair genes. Preventing the ability of macrophages to phagocytose apoptotic cells in vitro by deleting the receptor tyrosine kinases AXL and MERTK decreased expression of resolution and repair genes in macrophages. Finally, deletion of AXL and MERTK decreased resolution of inflammation and tissue repair in multiple tissues and disease contexts, including the lungs during helminth infection, the gut upon induced colitis, and the peritoneum after thioglycolate challenge. In total, this emerging paradigm, in which type 2 cytokines instruct tissue repair only when combined with the engagement of sensors of apoptotic cells, is likely to ensure that the transition to resolution does not happen simply because of the presence of cytokines or dead cells individually and safeguards against the healing of infected wounds. Figure attribution by users A. Rad, Mikael Häggström, Spacebirdy, RexxS, domdomegg [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons.Type 2 cytokines instruct tissue repair only when combined with the engagement of sensors of apoptotic cellsNews items were written by medical writer Jared Travers.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. Type 2 cytokines instruct tissue repair only when combined with the engagement of sensors of apoptotic cells News items were written by medical writer Jared Travers. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.