CAAIF/Pediapharm, a division of Medexus Pharmaceuticals Inc. Research Grant in Allergic Diseases
Dr. Kelly McNagny
Prediction of childhood allergic disease from alterations in umbilical cord cell signatures
Allergic asthma is a pathological condition where normally innocuous antigens generate an exaggerated inflammatory response. Why only certain individuals develop this condition is still unclear but both genetic predispositions as well as environmental exposures likely contribute. Recent evidence suggests that alterations in early life exposure to bacteria can have a profound influence on susceptibility to allergic asthma but the mechanisms remain unclear. It is also unclear whether alterations in maternal exposure to microbial products can alter future susceptibility of the offspring. To address this question my lab has leveraged access to cord blood samples from the Canadian Healthy Infant Longitudinal Development (CHILD) study, a study that provides archived biological samples from children who did or did not develop allergic disease. Our hypothesis was that if maternal exposures did predispose new born children to allergic disease we might see differences in their blood cells at birth. To perform the analyses we have developed a panel of cellular biomarkers that can be evaluated at the single cell level (Allergy CyTOF Antibody Panel, ACAP). In a preliminary experiment we were able to see expansion of 3 cell types selectively in the kids that were at risk for allergic asthma. Thus, this pilot study suggests that allergic asthma susceptibility may have been established before birth. The goal will now be to confirm this result with a larger number of samples from kids that we know are allergic and also to do further high throughput genomic analyses on those samples in order to understand the molecular pathways that establish this susceptibility. Importantly, this work would suggest that the most critical time for intervening in susceptibility to future allergic disease would be during pregnancy and could provide an opportunity to develop safe, non-invasive methods for decreasing susceptibility based on modulating maternal exposures to the environment.
CAAIF Top 10 Challenge Food Allergy Research Grant
Dr. Manel Jordada
Immune re-programming in peanut allergy
There is no cure for peanut (PN) allergy. Current treatment consists of strict avoidance of the culprit food and rescue epinephrine following accidental exposure, neither of which address the root of the disease. A number of oral immunotherapy (OIT) clinical trials for PN have been conducted. Favorable outcomes of OIT include desensitization and sustained unresponsiveness (SU). Lack of symptoms upon exposure to the allergen, while maintaining consistent low dose consumption, is termed desensitization. SU occurs if this state persists for 1-3 months beyond cessation of OIT. The efficacy of PN-OIT is limited by its safety profile which has recently been systematically reviewed in the PACE study. Therein, it was established that OIT increased the risk of anaphylaxis, epinephrine use, and other allergic symptoms compared to the current standard of care (strict avoidance). Consequently, PN allergy in particular, and food allergy in general, is in dire need of novel, transformative therapeutic approaches
This project is an extension of the funded 2018-19 CAAIF
-AAIA grant wherein we proposed to establish a human in vitro experimental system using peripheral blood mononuclear cells (PBMCs) that would be capable of evaluating both T and B cell responses, notably IgE in the case of the latter. In addition, we proposed to investigate the impact of an anti-IL-4Ra antibody treatment in PBMCs from PN allergic individuals. We have succeeded in these objectives and gone much further in that we have demonstrated that treatment with this antibody has a remarkable effect on the immune response to PN. A paper will be submitted in the coming weeks to Science Translational Medicine. However, important questions remain to be addressed.
Aralez Canada Pharmaceutical Inc. and CAAIF Research Grant in Allergic Rhinitis or Urticaria
DR. MOSHE BEN-SHOSHAN
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.
CIHR-ICRH/CAAIF/AstraZeneca/AllerGen Emerging Research Award in Allergic Asthma
DR. MANALI MUKHERJEE
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 Researcher Award in Allergic Asthma
DR. ADIL ADATIA
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.
CAAIF Knowledge Mobilization Award
DR. KYLA HILDEBRAND
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.
Asthma Canada/CAAIF Graduate Student Awards
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.