Dr. Kelly McNagny

Dr. Manel Jordana

Anthony Altieri

Aubrey Michi

 

Marie Marotel

Louis Marois

 

Brianne Philipenko

Allergic Rhinitis Grant

Early Investigator Award

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 Jordana

                                 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.

 

Asthma Canada/CAAIF Graduate Student Awards

Anthony Altieri

                           Regulation of Airway Inflammation: Cytokine IL-17 &

                            Cathelicidin LL-37

Asthma is a heterogeneous respiratory disease characterized by airway inflammation. The severity of inflammation reflects the progression and/or onset of the disease. Individuals with late-onset, severe asthma typically have high levels of immune cells called 'neutrophils' and 'T-helper-17 lymphocytes' in the lung compared to individuals with moderate asthma. These cells produce molecules called 'Cathelicidin LL-37' and 'Interleukin-17' respectively. The interplay of these molecules enhances the severity of asthma and causes patients with severe, late-onset asthma to respond poorly to already existing therapeutics, such as inhaled corticosteriods (ICS). My project will identify how the combination of these molecules exacerbates severe, late-onset asthma. As a result, therapeutic strategies can be created for individuals with severe asthma, who currently have limited treatment options.

 

Asthma Canada/CAAIF Graduate Student Awards

Aubrey Michi

                               Evaluation of trained innate immunity to rhinovirus infections in                                        highly-differentiated asthmatic airway epithelial cells

Respiratory viral infections have taken center stage as a global health emergency. As asthmatics are a vulnerable group for serious COVID-19 complications, we are reminded that non-coronavirus respiratory viruses, such as human rhinoviruses (HRV), also pose serious health risks to asthmatics. Repeated cold virus infections during early childhood are strongly associated with wheezing illnesses and asthma development. In particular, the HRV-C genetic group of rhinoviruses are strongly linked to severe asthma outcomes and hospitalizations in children. Since all children experience numerous seasonal colds, yet not all children develop asthma, we propose that the asthmatic airways may mount a dysfunctional immune response to repeated rhinovirus infections. This may result in permanent changes in the airway cells that contribute to creating an asthmatic airway in childhood. This project investigates the phenomenon of “trained” innate immunity, in which exposure to multiple rhinovirus infections may reprogram infected airway cells to fight future infections more efficiently. Potentially, asthmatic epithelial cells may not undergo this beneficial “training” to fight repeated infections, which could explain how repeated rhinovirus infections may instigate childhood asthma development.

 

CAAIF-CSACI Research Fellowship in Allergy and Clinical Immunology

Marie Marotel

                             Identification of novel molecular targets driving NK cell exhaustion

 

In addition to fighting infections, our immune system is very well equipped to also eliminate cancer cells. However, immune cells can get tired when they try to kill tumor cells for a prolonged time, something we call, quite literally, “exhaustion”. When they are exhausted, immune cells lose their ability to effectively kill tumor cells or to interact with each other. Unfortunately, the molecular mechanisms that underlie the establishment of immune exhaustion are not clear, and it is therefore hard to therapeutically revert immune exhaustion. Thanks to support from CAAIF, we will investigate these mechanisms and will discover genes and proteins that can be targeted to help immune cells re-gain stamina, exit the exhausted state and start killing cancer cells again. Discoveries from this project will help design more effective cancer immunotherapies that will allow our immune system to better fight cancer. 

 

CAAIF-CSACI Research Fellowship in Allergy and Clinical Immunology

Louis Marois

                        Identification of novel molecular targets driving NK cell exhaustion

Primary immunodeficiencies (PID) include more than 400 rare and heterogeneous diseases caused by genetic abnormalities or by the development of autoantibodies, conferring an increased susceptibility to infections, cancers, auto-inflammation. or autoimmunity. The classification of PIDs has recently formed a group of pathologies, the Primary Immune Regulation Disorders (PIRD), which, unlike classical PIDs which present themselves mainly by infections, mainly have autoimmune manifestations, reflecting the immune dysregulation of these patients. Despite the fact that infections and autoimmunity represent major complications in patients with PIRDs, little is known about the mechanism of penetrance of the PIRD phenotypes, of PIRD‑specific inflammation pathogenesis and even less is understood about the role of the microbiota both as a consequence and modulator of immune response in these inherited disorders.

 

For decades, PID researchers have focused on identifying the causative gene or protein for a given PID in order to determine the appropriate treatment. However, we believe that research should also be carried out to understand the factors that influence the frequency and severity of symptoms and to put in place strategies to reduce relapses and their importance in order to improve the quality of life of those affected. We want to assess the intrinsic and extrinsic factors that may affect the expression of the phenotype of patients with PIRD. To achieve this, we will attempt to qualitatively and functionally characterize the microbiome, transcriptome and metabolome of PIRD patients. In addition, we will examine the host-microbial interactions in PIRD-associated inflammation or autoimmunity.

  

CAAIF-CSACI Research Fellowship in Allergy and Clinical Immunology

Brianne Philipenko

                            Phenotyping disease severity in asthma: molecular investigations                             of corticosteroid resistance with the aim of improving patient                                     management

Inhaled corticosteroids (ICS), either as monotherapy or in combination with long-acting β2 agonists (LABA), are the mainstay of treatment in asthma to control airway inflammation and airway dysfunction. While ICS provides adequate control in patients with mild to moderate disease, these therapies are less effective in severe asthma. By following a guideline-based stepwise approach of treatment escalation there are often extended periods during which both the underlying airway inflammation and the asthma symptoms remain uncontrolled in these patients with severe asthma. This can lead to permanent damage, often termed airway remodeling, which results in fixed airflow obstruction that is no longer amenable to medical therapy. The ability to identify the molecular signature associated with ICS-resistant severe asthma should enable a more direct transition to appropriate therapies, thereby providing benefit both to patients and the health care system.

 

The funding provided by CAAIF will allow us to characterize the genes in severe asthmatics that are either resistant to ICS or, alternatively, induce even more inflammation. This could allow us to identify patients earlier who will be categorized as having severe asthma, and provide improved insight as to the most appropriate therapeutic strategy to be adopted for each patient. Finally, we hope to highlight novel therapeutic targets in severe asthma.  

PO Box 1333

Toronto, ON

M5M 0A1

Registered Charity Number : 89757 2152 RR0001