Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment
Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma.
AstraZeneca and its global biologics research and development arm, MedImmune, today announced that the US Food and Drug Administration (FDA) has approved Fasenra (benralizumab) for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.
Pascal Soriot, Chief Executive Officer of AstraZeneca, said: “We’re excited to offer Fasenra as a new precision biologic to help improve the lives of severe asthma patients whose disease is driven by eosinophilic inflammation. This is the first approval from our respiratory biologics portfolio and the latest in a series of significant milestones for our company as we deliver on our pipeline-driven transformation.”
The FDA approval is based on results from the WINDWARD programme, including the pivotal Phase III exacerbation trials, SIROCCO and CALIMA, and the Phase III oral corticosteroid (OCS)-sparing trial, ZONDA. Results for the 8-week benralizumab dosing regimen from these trials showed:
Up to 51% reduction in the annual asthma exacerbation rate (AAER) versus placebo
Significant improvement in lung function as measured by forced expiratory volume in one second (FEV1) of up to 159mL versus placebo. Differences were seen as early as 4 weeks after the first dose, providing an early indication of effectiveness
75% median reduction in daily OCS use and discontinuation of OCS use in 52% of eligible patients
An overall adverse event profile similar to that of placebo
Eugene Bleecker, MD, Professor and Co-Director, Genetics, Genomics and Precision Medicine, University of Arizona Health Sciences, and lead investigator of the pivotal Phase III SIROCCO study, said: “This is an important day for severe, eosinophilic asthma patients who have had limited treatment options for far too long, with many relying on oral steroids to manage their symptoms. Fasenra has a strong clinical profile which includes the ability to show lung function improvement after the first dose, the potential to reduce – or even stop - oral steroid use, and the convenience of 8-week dosing. Fasenraalso treats a distinct patient phenotype, helping physicians select the right patient in clinical practice with more confidence.”
Fasenra is the only respiratory biologic that provides direct, rapid and near-complete depletion of eosinophils within 24 hours. Eosinophils are a type of white blood cell that are a normal part of the body's immune system. Elevated levels of eosinophils, seen in about half of severe asthma patients, impact airway inflammation and airway hyper-responsiveness, resulting in increased asthma severity and symptoms, decreased lung function and increased risk of exacerbations.
Fasenra binds directly to the IL-5α receptor on an eosinophil and uniquely attracts natural killer cells to induce apoptosis (programmed cell death). Fasenra will be available as a once every 8-week fixed-dose subcutaneous injection via a prefilled syringe.
On 10 November, 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending the marketing authorisation of benralizumab. Benralizumab is also under regulatory review in Japan and several other countries.
San Diego Team wins $ 6.9 million grant to establish PrecISE Network Clinical Center
A collaboration between La Jolla Institute and UC San Diego School of Medicine, the center will connect patients, clinicians and researchers to develop personalized treatments, find a cure for asthma
November 6, 2017
LA JOLLA, CA— A team of physicians, scientists and biostatisticians joined forces across institutions to successfully compete for an $6.9 million grant to establish one of only 10 PrecISE Network Clinical Centers nationwide.
The PrecISE (short for Precision Interventions for Severe and/or Exacerbation Prone Asthma) Network is an initiative funded by the National Institutes of Health/National Heart, Lung and Blood Institute to advance precision medicine for patients with severe and exacerbation-prone asthma. It brings together patients, clinicians and researchers to accelerate the development of individualized asthma treatments based on patient-specific disease markers.
Starting in early 2018, the PrecISE Clinical Center will begin recruiting asthma patients in an effort to collectively enroll 1,000 patients in the nationwide PrecISE clinical trial. The study will rely on extensive data collection and analysis to help refine interventions while the trial is still ongoing. Known as adaptive trial design, the PrecISE asthma trial platform represents a novel approach in asthma clinical research.
The San Diego-based team is led by Praveen Akuthota, M.D., Associate Clinical Professor in the Division of Pulmonary, Critical Care and Sleep Medicine at UC San Diego School of Medicine; Pandurangan “Vijay” Vijayanand, M.D. Ph.D., William K. Bowes Distinguished Professor at La Jolla Institute for Allergy and Immunology, and Sonia Jain, Ph.D., Professor of Biostatistics in the Department of Family Medicine and Public Health at UC San Diego School of Medicine.
Dr. Akuthota runs both an active laboratory where he studies asthma and a clinical practice at UC San Diego Health where he sees patients. He said caring for asthma patients serves as a constant reminder how frustrating it can be to get the disease under control: “It is more or less a guessing game. We just keep trying different things until we hit upon a drug or drug combination that works. We need to be able to predict who will benefit from a certain treatment so we can reliably control symptoms and prevent potentially lethal asthma attacks.”
Dr. Vijayanand’s research tries to do just that. His research team employs innovative genomic tools to distinguish different disease states in asthma and pave the way for patient-specific asthma treatments. “The technology we now have access to in the laboratory not only helps us to understand the fundamentals of this disease,” said Dr. Vijayanand, “we are now able to apply our results on an individual level.”
Dr. Jain proposed the design for the adaptive clinical trial platform and will lead the center’s quantitative effort on design development and the analysis of the various types of data that will be generated in these multi-year adaptive trials. She will also play an integral role within the PrecISE Network’s ten centers to help fine-tune successive stages of the adaptive clinical trials. “It is exciting to be directly involved in creating an innovative clinical trial infrastructure that will yield important efficacy and safety data on novel asthma interventions,” says Dr. Jain, “I look forward to participating in this work and seeing how it directly impacts asthma patients.”
Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4+ T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3promoter region in CD4+ T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants.
Allergic asthma and rhinitis are two common chronic allergic diseases that affect the lungs and nose, respectively. Both diseases share clinical and pathological features characteristic of excessive allergen-induced type 2 inflammation, orchestrated by memory CD4+ T cells that produce type 2 cytokines (Th2 cells). However, a large majority of subjects with allergic rhinitis do not develop asthma, suggesting divergence in disease mechanisms. Because Th2 cells play a pathogenic role in both these diseases and are also present in healthy nonallergic subjects, we performed global transcriptional profiling to determine whether there are qualitative differences in Th2 cells from subjects with allergic asthma, rhinitis, and healthy controls. Th2 cells from asthmatic subjects expressed higher levels of several genes that promote their survival as well as alter their metabolic pathways to favor persistence at sites of allergic inflammation. In addition, genes that enhanced Th2 polarization and Th2 cytokine production were also upregulated in asthma. Several genes that oppose T cell activation were downregulated in asthma, suggesting enhanced activation potential of Th2 cells from asthmatic subjects. Many novel genes with poorly defined functions were also differentially expressed in asthma. Thus, our transcriptomic analysis of circulating Th2 cells has identified several molecules that are likely to confer pathogenic features to Th2 cells that are either unique or common to both asthma and rhinitis.