Translating Discoveries in IgE Memory to Transform Food Allergy Assessment and Management
Food allergy is a growing health problem that affects approximately 7.5% of Canadians and can cause life-threatening systemic reactions termed anaphylaxis. Some food allergies, such as those to peanut (PN) and shellfish are typically lifelong and more often associated with anaphylaxis - PNs are the leading cause of severe food related allergic reactions and fatalities. Without a cure for food allergy, the mainstay of therapy is allergen avoidance. There are two fundamental limitations to this approach: 1) Despite attempts at avoidance, there is a high rate of accidental ingestion (12% per year to PN), and 2) it does not address the source of the disease. Taken together, there are major challenges in the risk reduction, management, and mechanistic understanding of food allergy. In this proposal, we aim to translate recent discoveries in PN allergy from mice, described below, to humans by embedding immunological experimentation within two key clinical studies. In addition to the direct clinical impact of these two studies, this proposal will evaluate the utility of IgE memory B cells (MBCs) as risk stratification, response to therapy, and predictive tools for food allergy. This foundational work will also inform the candidacy of MBCs as a novel therapeutic target in allergy.
CAAIF/CSACI/AllerGen Emerging Clinician-Scientist Award
Dr. Derek Chu
Induction of immunologic tolerance of food allergens by use of regulatory dendritic cells
The outcomes of food allergies can range from hives to fatal anaphylaxis. While allergen avoidance fully prevents these reactions, vanishingly low-level exposure to some allergens can trigger lethal responses. Specific immunotherapy (SIT) has proven useful for some allergies, but SIT is cumbersome, dangerous if not used correctly, and is not uniformly effective. Oral immunotherapies (OIT) for food allergies have attracted a great deal of attention lately and they can dramatically increase the dose of allergen required to induce allergic reactions, but OIT also comes with very significant caveats. We have developed a novel, regulatory dendritic cell (DCreg) therapy that can reverse asthma and food allergies in animal models, and have now shown that human DCreg can reverse allergen sensitivity among T cells of allergic individuals. We propose to develop human DCreg for use in food allergic individuals, as assessed in vitro and, funds permitting, in vivo in humanized mouse models.
CAAIF Food Allergy Research Grant
DR. JOHN GORDON
Investigating treatment of Children with Chronic Hives
Urticaria (acute and chronic) is the fourth most prevalent allergic condition after rhinitis, asthma and drug allergy,but the number of patients who visit emergency departments due to urticaria is higher compared to these otherallergic diseases. Children with chronic urticaria (CU) have a substantial impairment of Health-related quality of life(patients suffering from CU scored in the lowest 25th percentile on physical impact) and significantly lower schoolperformance compared with the impact of other allergic diseases. Although no studies assessing the prevalence ofCU in Canadians had been published so far, assuming a similar 3% lifetime prevalence found in other countries, it islikely that over 1,000,000 Canadians will be affected by CU at some point in their life. The primary treatment for CUis high doses (up to 4 times normal dose) of antihistamines. However in many patients this does not bring relief.These cases are often prescribed omalizumab as an alternative treatment. We are interested in determining factorsimplicated in these cases where high dose antihistamines are not effective as well as the effectiveness of thealternative treatment.
Aralez Canada Pharmaceutical Inc. and CAAIF Research Grant in Allergic Rhinitis or Urticaria
DR. MOSHE BEN-SHOSHAN
Investigating autoimmune responses to tailor biologic therapies in severe asthma
Asthma can be very severe for approximately 10% of patients who suffer from significant symptoms, frequent hospitalizations, loss of productivity/income, and improve a significant economic burden. Severity is driven by a type of white blood cells (eosinophils) that gets recruited to the lungs as a result of allergy and other triggers and plug the airways. This is treated with glucocorticosteroids (prednisone) which causes serious side effects. Antibodies (biological) have been developed that blocks specific proteins which mediates allergy and further recruits these eosinophils to the lungs. However, for a number of reasons, they are not equally effective for all patients. Our research shows that antibodies in the airways of some patients may interfere with the action of these biological. This project will investigate how antibodies might mediate these effects and develop strategies to identify patients in whom these biological may not work.
CIHR-ICRH/CAAIF/AstraZeneca/AllerGen Emerging Research Award in Allergic Asthma
DR. MANALI MUKHERJEE
Inhibition of group 2 innate lymphoid cells as a therapeutic strategy in severe asthma
Our body’s immune system usually fights infections, but in many diseases it can attack the body itself, which is called autoimmunity. Autoimmunity is not well understood in asthma but appears to play a role in patients with severe asthma that involve eosinophils, a type of white blood cell. These severe asthmatics with eosinophils are treated with a drug called prednisone (corticosteroid), though it has many side effects and may not be fully effective. There is evidence of autoimmunity in the lungs of certain severe asthmatics who need prednisone chronically. They also have larger numbers of white blood cells called group 2 innate lymphoid cells (ILC2), which may play a role in their requirement for prednisone. These cells are also increased in asthma patients after they inhale a protein to which they are allergic. One of the proteins that activate ILC2 is called TL1A, and we thus propose a trial to see if blocking TL1A improves the disease control of asthmatics with eosinophils and autoimmune responses, with and without allergy.
CIHR-ICRH/CAAIF/AstraZeneca/AllerGen Emerging Researcher Award in Allergic Asthma
DR. ADIL ADATIA
Prevention of Food Allergy Knowledge Moblization
Food allergy places a significant burden on families and the public health system. The aim of this knowledge mobilization project is to develop an online, case-based educational module directed towards primary health care providers and public health practitioners with the recent evidence for early introduction of foods to infants in the prevention of food allergy. A pre and post participation questionnaire and follow up survey will be taken by all participants and results will be analyzed to see if providers improved in confidence and competence in counselling parents and caregivers of infants around early introduction of foods. By potentially reducing the number of infants who may develop food allergy through early introduction of foods, increased capacity within the specialty may be facilitated to shift towards offering upcoming and potentially curative therapies for food allergy.
CAAIF Knowledge Mobilization Award
DR. KYLA HILDEBRAND
Nociceptor neurons control pollution-exacerbating asthma
Half of the severe asthma patients suffer from uncontrolled exacerbations. Although several classes of drugs control asthma symptoms and help abort attacks, there is no available treatment that accelerates the resolution of inflammation. Recent advances suggest that airway pollution, including fine particular matter (FPM), exacerbates severe allergic airway inflammation (AAI). Our work in neuro-immunology has shown that, in the context of asthma, vagal nociceptor neurons drive a feed-forward inflammatory loop with lung immune cells, and that silencing these neurons reverses AAI. Recent data highlight neuronal expression of aryl hydrocarbon receptor (AhR) sensing of air pollution to the induction of atopic dermatitis. Overall, by acting upstream of lung type 2-inflammatory immune cells, targeting vagal AhR-nociceptors may constitute a promising therapeutic avenue to resolve pollution-exacerbating AAI.
Asthma Canada/CAAIF Graduate Student Awards
Understanding the role of the human gut virome in the development of early-onset asthma
The microbial composition of the human gut has received a great deal of attention in the past decade due to its implications in health and diseases. While the vast majority of research focuses on bacteria, phages are also found in the gut where they outnumber bacteria by a factor of ten. Phages are known to massively kill bacterial populations and interact with our immune system. Recently, our collaborators at EarlyVir (Denmark) have found robust evidence that a skewed bacterial composition in the gut during the first year of life affects the risk of early-onset asthma. But what about gut phages? Given their abundance in this ecosystem, do phages play a role in the development of asthma? The impact of phages on our health remains poorly understood in general as their characterization is challenging and requires tailored and multidisciplinary approaches.