Category: Asthma Studies

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Study assesses asthma treatment options in African American children and adults

Use of long-acting bronchodilators had no impact for some African American children.

A new study of African Americans with poorly controlled asthma, found differences in patients’ responses to commonly used treatments. Contrary to what researchers had expected, almost half of young children in the study responded differently than older children and adults, and than white children in prior studies.

“We shouldn’t assume that current treatment strategies for asthma are ideal for all African Americans since for many years that population was not adequately represented in research,” said Elliot Israel, M.D., senior study author and director of clinical research in the Pulmonary and Critical Care Medicine Division at Brigham and Women’s Hospital. “We found that almost half of the African American children studied responded better to increasing the dose of inhaled corticosteroids than adding a long-acting bronchodilator. Thus, adding a long-acting bronchodilator may not be the right answer for nearly half of African American children.”

The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, funded this research to assess the best approach to asthma management in African Americans, who suffer much higher rates of serious asthma attacks, hospitalizations, and asthma-related deaths than whites. The findings appear today in the New England Journal of Medicine.

The researchers examined how to escalate or “step-up” asthma treatments for African Americans whose asthma had not been treated adequately with low doses of inhaled corticosteroids, the standard starting treatment. The treatment choices in the trial included increasing the dose of inhaled steroid, adding a long-lasting bronchodilator (used to help open airways), or both.

Based on prior studies, investigators expected that increasing the inhaled corticosteroid dose would lead to improvement in most African American children needing treatment for asthma.

The researchers found that in children under 12 years of age, either approach was effective: nearly half (46%) responded better to increasing the inhaled corticosteroid dose alone and just as many (46%) responded better to increasing the inhaled corticosteroid dose and adding a long-lasting bronchodilator.

“This study suggests that we cannot look at results from one population and extrapolate the findings to African Americans or any other group,” said Michael Wechsler, M.D., principal investigator for the NHLBI-funded Best African American Response to Asthma Drugs (BARD) study and professor of medicine at National Jewish Health in Denver. “If children do not respond to one treatment, parents and providers could consider another option because there is almost a 50% chance of having a better response.”

The multicenter study included 574 participants — about half of whom were ages 5–11 and half 12 years and older. All participants in this study had at least one self-identified African American grandparent, with an average of approximately 80% African ancestry, based on genetic testing.

Of the adolescents over 11 years old and adults, most (49%) responded better to adding a long-lasting bronchodilator than to increasing the inhaled corticosteroid dose, though 20–25% in this group showed no difference in their responses to these approaches.

Investigators also examined whether patient characteristics, including genetic ancestry, could be used to predict the response to the “step-up” treatments in the study participants. But they were unable to use genes indicative of African ancestry, or any of the other patient characteristics they measured in this group of patients, to predict treatment response.

“Although we cannot attribute the study’s findings to genetic markers of African ancestry, there could be as-yet unknown genetic variants specific to people of African descent that affect how severe a patient’s asthma is,” said Wechsler.

Before the trial began, the researchers did not expect the participants to have a better response to treatment regimens that included long-lasting bronchodilators, despite the inclusion of these agents in treatment recommendations. They said they were surprised that many (46% of the young children and 49% of the older children and adults) improved with long-lasting bronchodilators.

“These results provide new data about the management of asthma patients who self-identify as African American regardless of genetic ancestry,” said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. “Every person and their provider should explore all of their management choices to achieve maximum asthma control, based on their response to specific medications.”

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit https://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Protein found in patients with severe asthma can help identify who would benefit from targeted drugs

Novel study establishes that airways periostin is the expression of type 2 endotype severe asthma and helps identify which patients may benefit from newly developed treatments and improved quality of life, report researchers in the journal CHEST®

Glenview, IL, October 22, 2018 – In a novel study, researchers succeeded in identifying patients with a form of severe asthma (type 2 endotype) by measuring periostin concentrations in their airways. These patients with the type 2 (T2) endotype may benefit from newly developed targeted treatments that have the potential to transform their quality of life, report researchers in the journal CHEST®.

Asthma can range from very mild with little or no need for medical treatment to severe and life-threatening. Severe asthma is clinically and biologically varied and identifying the specific type of asthma is crucial in targeting patients who will benefit from new treatment options. The role of periostin, a matricellular protein, in asthma and type 2 inflammatory responses, is an area of active research.

“The T2 immunity severe asthma endotype is one of the most consistent endotypes to emerge probably because it is a key driver in nearly half of all patients with asthma,” explained Giovanna E. Carpagnano, MD, PhD, Institute of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Investigators analyzed periostin concentrations in the airways of severely asthmatic subjects, evaluating the role of periostin in clustering the T2 endotype. They enrolled 40 consecutive severe asthmatic patients (25 asthmatics of T2 and 15 of non-T2 endotype); 21 patients with mild to moderate asthma; and 15 healthy control subjects. All individuals underwent exhaled breath condensate and sputum collection, eosinophil count in blood, fractional 32 exhaled nitric oxide (FeNO) and immunoglobulin E (IgE) measurement. They found that periostin is measurable in the airways and increased in severe asthmatic subjects, especially in those with the T2 endotype.

“There have been several studies about the value of periostin as a marker of severe eosinophilic asthma, but to measure it in blood limits its value as serum periostin derives from several sources outside the lung and can’t be considered an organ-specific marker,” noted Maria Pia Foschino Barbaro, MD, Institute of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy, who heads the group where the research was conducted.

“Unlike serum periostin, airways periostin is a useful marker of severe eosinophilic asthma and may help to phenotype patients that will respond to the biologic agents,” stated senior investigator Peter J. Barnes, MD, DSc, FCCP, of the Airway Disease Section, National Heart and Lung Institute, Imperial College London, UK. “The newly developed biological treatments have the potential to transform the quality of life of patients with T2 severe asthma. This study suggests that airways periostin is the expression of T2 severe asthma and if validated, could be a useful biomarker to apply stratified medicine for severe asthma, and could transform the quality of life of these patients.”

“Severe uncontrolled asthma is an expensive disease that accounts for more than 60 percent of the costs associated with the disease,” commented Prof. Carpagnano. “The newly developed biological treatments are expensive too, but if directed to the right patients, they will significantly reduce the global cost related to the management of severe asthmatic patients.”

Credit: CHEST®

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Asthma and Bacteria: Exposure May Help Body Beef Up Immunity, Study Says

Asthma and Bacteria: Exposure May Help Body Beef Up Immunity, Study Says

The research was done in mice, but it supports the “hygiene hypothesis”: the idea that bacteria are needed to shape a healthy immune system, and that our bacteria-fearing lifestyles are increasing levels of asthma, allergy and other autoimmune diseases.

In the study, which was published in the journal Science, the researchers compared normal mice with mice that were raised in special germ-free environments. They found high levels of special white blood cells called invariant natural killer T cells (iNKT) in the lungs and intestines of the germ-free mice.

These iNKT cells release proteins that cause inflammation and attract more inflammatory white blood cells. Inflammation plays an important role in many autoimmune diseases, and iNKT cells are known to be an active ingredient in asthma, which is in the lungs, and ulcerative colitis, an inflammatory disease of the bowel.

Even when exposed to normal bacteria later in life, the germ-free mice still had abnormally high levels of iNKT cells and diseased lungs and intestines. This indicated that an “immune priming event” happens very early in life and is essential for the proper formation of the immune system, the researchers said.

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Asthma Study: Getting Patients to Take Their Asthma Meds

Asthma Patients More Likely To Take Meds Under Physician Supervision

Armed with the right information, physicians can play a stronger role in ensuring asthma patients don’t waver in taking drugs proven to prevent asthma attacks, according to researchers at Henry Ford Hospital in Detroit.

The study finds patients are more likely to routinely take inhaled corticosteroids (ICS) for asthma control when physicians kept close watch over their medication use and reviewed detailed electronic prescription information, including how often patients fill their prescriptions and the estimated number of days each prescription would last.

“Better inhaled corticosteroid adherence means better overall asthma control, and less hospitalization,” says lead study author L. Keoki Williams, M.D., MPH, Center for Health Services Research and Department of Internal Medicine at Henry Ford Hospital.

“Unfortunately, overall patient adherence to ICS medication is poor, accounting for an estimated 60 percent of asthma hospitalizations. So it’s important, as we move forward with health care reform, to look for more effective ways to make sure patients stay with their prescription regimens.”

The study – the first large-scale, controlled study to test the effectiveness of routinely providing patient medication adherence information to physicians – appears online in the Journal of Allergy and Clinical Immunology (www.jacionline.org).

ICS, taken using an inhaler, help prevent and reduce airway swelling, and are considered the cornerstone therapy for controlling persistent asthma in patients, says Dr. Williams.

The Henry Ford scientific team set out to design an intervention that would provide physicians information on the most recent national asthma guidelines and methods for discussing medication non-adherence with their patients.

The intervention also offered physicians electronic access to patients’ medication prescription fill/refill information via Henry Ford’s ePrescribing application, part of its electronic medical record system that allows physicians to prescribe and review patient medications electronically.

The study enrolled 193 Henry Ford primary care physicians (family medicine, internal medicine, pediatrics). Eighty-eight were randomly assigned to the intervention group, while 105 were assigned to the control group (no intervention).

Physicians in the intervention group used ePrescribing to track medication fills and refills. The application also offered physicians the option to take it one step further: To review detailed adherence data, including estimates of the proportion of time that the patients took their medication.

Medication adherence for both groups was measured by using both electronic prescriptions and pharmacy claims for medication fills and refills.

Researchers found ICS adherence to be very similar among patients in the intervention group and those in the control group (21.3 percent vs. 23.3 percent).

But adherence was significantly higher in the intervention group (35 percent) when the patient’s physician elected to view detailed adherence information via the ePrescribing application.

Few physicians, however, in the intervention group accessed the detailed adherence information. “Going forward, one of the obstacles will be finding time for physicians to review and discuss this information with patients in their typically busy practices,” says Dr. Williams.

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Asthma and Pseudomonas Bacteria

Allergic Inflammation and Asthma Possibly linked to Pseudomonas Bacteria

Could some cases of asthma actually be caused by an allergic reaction to a common environmental bacteria? New research findings published in the Journal of Leukocyte Biology suggests that this is a possibility. In a research report appearing in the February 2012 print issue, researchers show a link between common environmental bacteria and airway inflammation. Specifically, their research suggests that some strains of Pseudomonas aeruginosa cause white blood cells to produce very high levels of histamine, which in turn leads to inflammation, a hallmark symptom of asthma.

In this five minute interview with Dr. George Caughey, M.D. Chief, Pulmonary/Critical Care/Sleep Medicine Section San Francisco VA Medical Center and Professor of Medicine at University of California, San Francisco (UCSF) School of Medicine we discuss the key studies findings, potential treatment options and laboratory test for Pseudomonas Bacteria.

“We hope that these findings in mice will encourage human-focused research regarding bacterial stimulation of histamine production by white blood cells, like neutrophils, that are not traditionally associated with allergic inflammation,” said Dr. George Caughey, M.D., a researcher involved in the work. “Such research could improve our understanding of inflammation in bacterial infections, and help us to craft therapies for relief of inflammation and its consequences for short and long-term health,” he noted. To make this discovery, scientists studied the effect of two strains of pseudomonas bacteria on isolated mouse white blood cells tasked with killing bacteria, called neutrophils.

To make this discovery, scientists studied the effect of two strains of pseudomonas bacteria on isolated mouse white blood cells tasked with killing bacteria, called neutrophils. Results showed that one strain killed the neutrophils, but the second strain produced substances that caused the neutrophils to increase their production of histamine significantly. To see if their discovery was applicable outside of the test tube, the histamine-stimulating strain was then used to infect mice to produce bronchitis and pneumonia. These mice experienced a significant increase of histamine in their airways and lungs. Additional work showed that the bacteria persuade neutrophils to produce histamine by causing them to make much more of the key enzyme in histamine synthesis (histidine decarboxylase) than neutrophils would otherwise do in the unstimulated state.

“Despite advances in diagnosing and treating the symptoms of asthma and allergy, our understanding of the underlying initiating events remains elusive,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “This report helps shed light on how an ‘everyday organism’ might trigger asthma and allergy from an immune cell type not normally thought to be involved in allergic disease.”

About the Journal of Leukocyte Biology

The Journal of Leukocyte Biology (http://www.jleukbio.org) publishes peer-reviewed manuscripts on original investigations focusing on the cellular and molecular biology of leukocytes and on the origins, the developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes and other cells involved in host defense and inflammation. The Journal of Leukocyte Biology is published by the Society for Leukocyte Biology.

About George Caughey, M.D.

Dr. Caughey received an M.D. from Stanford. After Medicine and Pulmonary subspecialty training at Pennsylvania Hospital and UCSF, he trained in lung research at UCSF’s Cardiovascular Research Institute and at Genentech, joining UCSF’s pulmonary faculty in 1986. He occupies the Julius and Lillian Nadel Endowed Chair and is Chief of the Pulmonary and Critical Care Medicine Section at the San Francisco VA Medical Center. Major activities include laboratory-based research, teaching, inpatient and outpatient clinical consulting, and serving on editorial, administrative, and advisory committees.

Research Interests
Extracellular proteases influence the pathology of lung diseases. The lab is interested in the roles of known and novel proteases in normal and diseased lung, emphasizing roles in scarring, ion transport, and anti-bacterial defense. The lab’s traditional focus is on peptidases secreted by mast cells, which are resident inflammatory cells especially abundant in human lung. The lab characterized several of the major secreted mast cell serine proteases. Achievements include the first cloning of a tryptase and discovery of new functions of these enzymes as peptidases, secretagogues and modulators of muscle tone. These investigations encouraged pharmaceutical development of tryptase inhibitors. The lab characterized the multi-gene human tryptase locus, discovering novel genes encoding membrane-anchored (gamma) and truncated (delta) tryptases, as well as major polymorphisms and population-skewed inheritance of deficiency alleles like alpha and frame-shifted beta. A current thrust of research concerns clinical consequences of human variations in inheritance of mast cell tryptase genes.

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Asthma Risk and Birth Weight Reported

Accelerated infant growth increases risk of future asthma symptoms in children says study from The Generation R Study Group at Erasmus Medical Center in the Netherlands.

According to the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine, accelerated growth in the first three months of life, but not fetal growth, is associated with an increased risk of asthma symptoms in young children. a

“We know that low birth weight is associated with an increased risk of asthma symptoms in children, but the effects of specific fetal and infant growth patterns on this risk had not been examined yet,” said researcher Liesbeth Duijts, MD, PhD. “In our study, weight gain acceleration in early infancy was associated with an increased risk of asthma symptoms in children of preschool age, independent of fetal growth patterns, suggesting that early infancy might be a critical period for the development of asthma.”

This study was embedded in the Generation R Study, a population-based prospective cohort study, and included 5,125 children who were followed from fetal life through the age of four. Information on asthma symptoms was obtained by questionnaires at the ages of 1, 2, 3, and 4.

No consistent relationships between fetal length and weight growth during different trimesters and the development of asthma symptoms were observed. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms, including wheezing (overall odds ratio (OR) 1.44 (95% confidence interval (CI): 1.22, 1.70), shortness of breath: 1.32 (1.12, 1.56), dry cough: 1.16 (1.01, 1.34), and persistent phlegm: 1.30 (1.07, 1.58)). The associations between accelerated infant growth and risk of developing asthma symptoms were independent of other fetal growth patterns and tended to be stronger among children of atopic mothers.

“Our results suggest that the relationship between infant weight gain and asthma symptoms is not due to the accelerated growth of fetal growth-restricted infants only,” said Dr. Duijts. “While the mechanisms underlying this relationship are unclear, accelerated weight growth in early life might adversely affect lung growth and might be associated with adverse changes in the immune system.”

The study had a few limitations, including the possibility of measurement error in the estimation of fetal weight and the use of self-report for asthma symptoms.

“Further research is needed to replicate our findings and explore the mechanisms that contribute to the effects of growth acceleration in infancy on respiratory health,” concluded Dr. Duijts. “The effects of infant growth patterns on asthma phenotypes in later life should also be examined.”

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Asthma Risk and Children Born by C-Section Study

Published reports in the American Journal of Epidemiology reflect that children delivered by Cesarean section appear to be at a slight increased risk of developing asthma by age 3.

According to press reports, researchers analyzed data from more than 37,000 participants in the Norwegian Mother and Child Cohort Study in order to compare the health of children who were delivered by planned or emergency C-section with those who were born vaginally.

The results showed that children delivered by C-section had a slightly increased risk for asthma at age 3, but no increased risk for wheezing or frequent lower respiratory tract infections. The risk of asthma was highest among those whose mothers did not have allergies.

According to the Norwegian Institute of Public Health, “It is unlikely that a Cesarean delivery itself would cause an increased risk of asthma, rather that children delivered this way may have an underlying vulnerability,” study primary author Maria Magnus, a researcher at the department of chronic diseases.

Possible reasons for the increased risk of asthma among children delivered by C-section include an altered bacterial flora in their intestine that affects their immune system development, or the fact that these children are more likely to

While the study found an association between C-section birth and asthma, it did not demonstrate a cause and effect.

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Asthma Study Offers Clues to Why Some Don’t Benefit From Asthma Meds

Press reports reflect that almost half of patients with mild or moderate asthma may have a different type of disease than those with more severe symptoms, perhaps explaining why common treatments don’t work well for them, new research suggests.

A large subgroup of mild-to-moderate asthma is persistently non-eosinophilic

A large percentage of patients with mild-to-moderate asthma have persistently non-eosinophilic disease which may not respond to currently available anti-inflammatory treatments, according to a new study.

In a cross-sectional study of 995 asthmatic subjects enrolled in nine clinical trials conducted by the NHLBI’s Asthma Clinical Research Network, sputum eosinophilia (?2% eosinophils) was found in only 36% of asthmatics not using an inhaled corticosteroid (ICS) and 17% of those using an ICS. Among patients who achieved good asthma control, 26% had sputum eosinophilia, compared with 15% among patients who had not achieved good control.

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

Among asthmatic subjects not taking an ICS who had repeated induced sputum samples, 22% had sputum eosinophilia on every occasion (persistent eosinophilia), 31% had eosinophilia on at least one occasion (intermittent eosinophilia), and 47% had no eosinophilia on every occasion (persistently non-eosinophilic). Two weeks of treatment with a combination of anti-inflammatory drugs resulted in significant improvements in airflow obstruction in subjects with eosinophilic asthma, but not in those with persistently non- eosinophilic asthma. Bronchodilator responses to albuterol, however, were similar in eosinophilic and non-eosinophilic asthma.

“Prevalence estimates for non-eosinophilic asthma in earlier studies were based on single sputum samples,” said John Fahy, MD, MSc, professor of medicine and director of the Cardiovascular Research Institute/University of California San Francisco Airway Clinical Research Center. “Here we show for the first time that sputum eosinophilia is persistently absent in a large percentage of patients with mild/moderate asthma when sputum is analyzed repeatedly over time.”

The poor response to intense combined treatment seen in patients with persistently non-eosinophilic asthma suggests that these patients have a unique disease phenotype for which new treatments need to be developed. Treatment responses in patients with intermittent eosinophilia were similar to those of patients with persistent eosinophilia.

“A large subgroup of patients with mild-to-moderate asthma do not have the usual eosinophilic subtype that is responsive to steroid treatment,” concluded Dr. Fahy. “In addition to the implications for the care of these patients, our results have important implications for future asthma research. In clinical studies, the eosinophil phenotype of patients should be characterized to better understand treatment responses and disease mechanisms. In addition, appropriate in vitro and animal models for the study of the mechanisms of non-eosinophilic airway disease need to be developed.”

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Molecular Pathway, Asthma Inflammation and Future Treatment Options

Researchers Identify Molecular Pathway that leads to Inflammation in Asthma

Researchers at the University of Pittsburgh School of Medicine have identified a molecular pathway that helps explain how an enzyme elevated in asthma patients can lead to increased mucus production and inflammation that is characteristic of the lung condition. Their findings, reported online in this week’s Proceedings of the National Academy of Sciences, reveal unique interactions between biological molecules that could be targeted to develop new asthma treatments.

An enzyme called epithelial 15-lipoxygenase 1 (15LO1) metabolizes fatty acids to produce an eicosanoid known as 15 hydroxyeicosaetetranoic acid (15 HETE) and is elevated in the cells that line the lungs of asthma patients, explained Sally E. Wenzel, M.D., professor of medicine, Pitt School of Medicine, and director of the Asthma Institute at UPMC and Pitt School of Medicine. Her team showed in 2009 that the enzyme plays a role in mucus production.

“In this project, we found out 15 HETE is conjugated to a common phospholipid,” she said. “That complex, called 15HETE-PE, and 15LO1 behave as signaling molecules that appear to have a powerful influence on airway inflammation.”

By examining lung cells obtained by bronchoscopy from 65 people with asthma, the researchers found that both 15LO1 and 15HETE-PE displace an inhibitory protein called PEBP1 from its bond with another protein called Raf-1, which when freed can lead to activation of extracellular signal-regulated kinase(ERK). Activated ERK is commonly observed in the epithelial, or lung lining, cells in asthma, but until now the reason for that was not understood.

“This is an important study as it directly explores the important role of 15-lipoxygenase 1 in the airway epithelial cells of patients with asthma, which immediately establishes the relevance to human disease,” said Mark T. Gladwin, M.D., chief, Division of Pulmonary, Allergy and Critical Care Medicine, UPSOM.

Other experiments showed that knocking down 15LO1 decreased the dissociation of Raf-1 from PEBP1, which in turn reduced ERK activation. The pathway ultimately influences the production of factors involved in inflammation and mucus production.

“These results show us on both a molecular and mechanistic level and as mirrored by fresh cells from the patients themselves that the epithelial cells of people with asthma are very different from those that don’t have it,” Dr. Wenzel said. “It also gives us a potential treatment strategy: If we can prevent Raf-1 displacement, we might have a way of stopping the downstream consequences that lead to asthma.”

Co-authors include Jinming Zhao, Ph.D., Silvana Balzar, M.D., Claudette M. St. Croix, Ph.D., and John B. Trudeau, B.S., of UPSOM and the Asthma Institute; and Valerie B. O’Donnell Ph.D., of Cardiff University, United Kingdom. The study was funded by the National Institutes of Health and the American Heart Association.

Contact: Anita Srikameswaran
SrikamAV@upmc.edu
412-578-9193
University of Pittsburgh Schools of the Health Sciences
Pitt team finds molecular pathway that leads to inflammation in asthma
75.26.195.212

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Why Does Flu Trigger Asthma?

Why Does Flu Trigger Asthma? Study suggests new therapeutic targets for virally-induced asthma attacks

When children with asthma get the flu, they often land in the hospital gasping for air. Researchers at Children’s Hospital Boston have found a previously unknown biological pathway explaining why influenza induces asthma attacks. Studies in a mouse model, published online May 29 by the journal Nature Immunology, reveal that influenza activates a newly recognized group of immune cells called natural helper cells – presenting a completely new set of drug targets for asthma.

If activation of these cells, or their asthma-inducing secretions, could be blocked, asthmatic children could be more effectively protected when they get the flu and possibly other viral infections, says senior investigator Dale Umetsu, M.D., Ph.D., of Children’s Division of Immunology.

Although most asthma is allergic in nature, attacks triggered by viral infection tend to be what put children in the hospital, reflecting the fact that this type of asthma isn’t well controlled by existing drugs.

“Virtually 100 percent of asthmatics get worse with a viral infection,” says Umetsu. “We really didn’t know how that happened, but now we have an explanation, at least for influenza.”

Natural helper cells were first, very recently, discovered in the intestines and are recognized to play a role in fighting parasitic worm infections as part of the innate immune system (our first line of immune defense).

“Since the lung is related to the gut – both are exposed to the environment – we asked if natural helper cells might also be in the lung and be important in asthma,” Umetsu says.

Subsequent experiments, led by first authors Ya-Jen Chang, Ph.D., and Hye Young Kim, Ph.D., in Umetsu’s lab, showed that the cells are indeed in the lung in a mouse model of influenza-induced asthma, but not in allergic asthma. The model showed that influenza A infection stimulates production of a compound called IL-33 that activates natural helper cells, which then secrete asthma-inducing compounds.

“Without these cells being activated, infection did not cause airway hyperreactivity, the cardinal feature of asthma,” Umetsu says. “Now we can start to think of this pathway as a target – IL-33, the natural helper cell itself or the factors it produces.”

Personalized medicine in asthma?

The study adds to a growing understanding of asthma as a collection of different processes, all causing airways to become twitchy and constricted. “In mouse models we’re finding very distinct pathways,” Umetsu says.

Most asthma-control drugs, such as inhaled corticosteroids, act on the best-known pathway, which involves immune cells known as TH2 cells, and which is important in allergic asthma. However, Umetsu’s team showed in 2006 that a second group of cells, known as natural killer T-cells (NKT cells), are also important in asthma, and demonstrated their presence in the lungs of asthma patients. NKT cells, they showed, can function independently of TH2 cells, for example, when asthma is induced with ozone, a major component of air pollution. Compounds targeting NKT cells are now in preclinical development.

The recognition now of a third pathway for asthma, involving natural helper cells, may reflect the diversity of triggers for asthma seen in patients.

“Clinically, we knew there were different asthma triggers, but we thought there was only one pathway for asthma,” Umetsu says, adding that all of the identified pathways can coexist in one person. “We need to understand the specific asthma pathways present in each individual with asthma and when they are triggered, so we can give the right treatment at the right time.”

The study was funded by the National Institutes of Health.

Children’s Hospital Boston is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children’s research community. Founded as a 20-bed hospital for children, Children’s Hospital Boston today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children’s also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Children’s, visit: http://vectorblog.org.

CONTACT:
Erin McColgan
Children’s Hospital Boston
617-919-3110
erin.mccolgan@childrens.harvard.edu