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Dr. Channakeshava Sokke Umeshappa
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CAAIF-Immunodeficiency Canada Research Fellow in Immunodeficiency
Dr. Ori Scott
Elucidating pathophysiology of auto-inflammatory disease mechanisms
in the inborn error of immunity STAT1 gain-of-function
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STAT1 is a gene that plays a critical role in the immune response against infections, and in particular against viruses. Because STAT1 is such an important gene, its activity is tightly regulated in most healthy people. STAT1 gain-of-function (GOF) is a genetic primary immunodeficiency, which is caused by increased activity of STAT1. The most common symptoms in patients with STAT1 GOF is chronic fungal infections, which are typically not life threatening. However, some STAT1 GOF patients also develop severe symptoms, such as lethal viral infections, or severe autoimmunity/auto-inflammation. In this work, we will use a mouse model to study what causes such severe disease manifestations in STAT1 GOF. Importantly, STAT1 activity can be disrupted even in people who do not have STAT1 GOF. For this reason, by researching STAT1 GOF, we can learn a lot about the development of severe infections, autoimmunity or inflammation even in people without STAT1 GOF. Ori is thankful to the Canadian Allergy, Asthma, and Immunology Foundation and Immunodeficiency Canada for their support of this work.
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This award was jointly funded by CAAIF and Immunodeficiency Canada
Allergic Airways Disease Innovation Grant
Dr. Paul Forsythe
Pulmonary Neuroendocrine Cells as targets for gene therapy in
asthma
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This study focuses on specialized cells in the lung called Pulmonary Neuroendocrine Cells (PNEC). PNEC are found in the surface lining of the lung (epithelium) and are very rare (less than 1% of cells in the epithelium) but play an important role in detecting changes in the content of the air we breathe (oxygen levels, pollutants, bacteria), allowing the lungs to respond and maintain healthy function. PNEC are increased in number in asthmatics and recent studies, in mice, suggest that these cells play a key role in causing asthma and/or making asthma symptoms worse. Our own preliminary work shows that, when exposed to allergens, PNEC start expressing Calcitonin Gene Related Peptide (CGRP), a neuropeptide known to enhance airway inflammation. By modifying CGRP gene expression in PNEC we may be able to control the airway inflammation associated with asthma. We propose that PNEC are strong candidates for gene therapy delivered directly to the lungs as they are anatomically located at the branching points of airways, ideally placed to interact with inhaled substances. Our study will set out to determine if PNEC are suitable and meaningful targets for inhaled gene therapies. We have established a method to produce human PNEC from induced pluripotent stem cells; allowing us to study the biology of a cell that is too rare to isolate from human lung tissue. We will use these stem cell derived human PNEC to develop lipid nanoparticle delivered gene therapy that can supress gene expression and production of proinflammatory CGRP. We will then test the efficacy of PNEC targeted gene therapy in a preclinical model of asthma. If successful, this project will be the first stage in the development of an entirely new approach to treating asthma with the possibility of reducing disease burden in those who do not respond to current treatments.
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This award was jointly funded by AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Allergic Airways Disease Innovation Grant
Dr. Bruce Mazer
Mitigation of Type 2 Asthmatic Inflammation using B-cell derived Extracellular Vesicles
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Extracellular vesicles (EVs) are produced by a wide variety of cells under many conditions, and their potential as intercellular communication molecules is an emerging area of study. There is paucity of work in understanding EVs in allergic diseases, how they contribute to the regulation of immune inflammation, and ultimately how EVs may be harnessed to address a therapeutic need for severe allergic airways disease. We have found in a mouse model of asthma that B-lymphocytes, stimulated under conditions that produce IgE, release large amounts of EVs that that appear to inhibit important facets of allergic inflammation, including eosinophil growth and inflammation in the airways of allergic mice.
Our CAAIF funded project will address for the first time the production of EVs using human B-cells and demonstrate their effects on the key asthma-related inflammatory cell, the eosinophil. We will determine the cellular and molecular impact of B-cell-derived EVs on eosinophil growth, maturation and function. B-cell derived EVs have extreme promise as a source of nanoparticles that can be delivered to the airways by aerosol and can inhibit eosinophil growth and other facets of Th2 inflammation via the expression of key surface receptors and inhibitory genetic material.
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This award was jointly funded by AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Allergic Airways Disease Innovation Grant
Dr. Channakeshava Sokke Umeshappa
Development of a novel, targeted, cell-based immunotherapeutic drug for asthma
The overall objective of this proposal is to develop a cell-based immunotherapeutic drug of ground-breaking significance for severe asthma.
The proper functioning of the lungs is vital for life. In asthma, the airways get damaged, compromising optimal performance and well-being and, when severe, shortening lifespan. It affects both adults and children, and can be a life-long problem. Asthma is the most common long-term respiratory illness. Across Canada, approximately 1 in 3 people has asthma, and nearly 4 million Canadians are living with asthma.
There are only a few specific drugs, unlike we have for bacterial infections, for asthma, perhaps because of the complex immune mechanisms involved. Severe asthma is treated generally by non-specific immunosuppressants such as steroids that suppress the whole immune system that is otherwise necessary for defending our body. Consequently, steroid therapy can adversely affect our immune system, increasing the risk of lung infections.
Asthma is caused by small particles present in the environment called allergens. Certain white blood cells respond to these allergens, become dangerous and damage airways. We will develop a cell-based anti-asthma treatment, which will kill these harmful white blood cells that respond to allergens, a long-sought-after goal in severe asthma therapy. We will test our drug’s therapeutic efficacy and safety using a well-established animal model of asthma, which facilitates our subsequent clinical translation of this therapeutic platform. The research will be pursued with a leading-edge interdisciplinary team of established scientists, clinicians, and trainees spanning the spectrum of synthetic biology, bioinformatics, and immunology.
By restoring normal lung functions in a disease-specific manner, without causing general immune suppression, our treatment should prevent asthma patients from getting chronic breathing problems and secondary infections, making Canada and the World a healthier place to live.
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This award was jointly funded by AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
CAAIF Research Fellowship in Immunology
Supported by Takeda Canda
Dr. Vanessa Polito
Phenotypic and genotypic characterization of hyper IgE immune dysregulation
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Abnormal functioning of the immune system, known as immune dysregulation, manifests in different ways. Patients can present with severe and recurrent infections, allergies, autoimmune disease, or malignancy. Allthough allergies are common, a subset of patients with severe allergies, known as atopic disease, may also have underlying abnormalities of their immune system. Atopic disease can be mediated by a specific antibody in the blood called IgE. A high level of IgE, as measured on a blood test, can be an indicator of atopy. In order to better understand this antibody's function, we are studying patients with high levels of IgE antibodies. We will collect data on their "phenotype" or the types of clinical problems they have. We will then perform genetic studies - known as whole exome sequencing. This will allow us to analyze the DNA building blocks, or genetic code, that may be causing these abnormally high levels of IgE antibodies and resulting immune dysregulation. We hope to characterize groups of patients by their phenotypes - for instance those that have infections, those those that have allergies, or those that are clinically well - and correlate this to the type of genetic changes they have in their DNA. The goal of this project is both to identify new genetic mutations causing these health problems, and to better diagnose and treat this group of patients. Ideally, we can better identify patients with this type of immune dysregulation to treat them more effectively.
CAAIF-CASP Research Grant in Hereditary Angioedema (HAE)
Dr. Stephen Betschel
Canadian physician hereditary angioedema management practice pattern survey
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Hereditary angioedema (HAE) is a rare but serious and potentially life-threatening condition due to random and unpredictable swellings involving extremities, face, abdomen, and the upper airway. This condition is associated with a significant impairment of quality of life. There have been significant advancements to prevent attacks and treat attacks when they occur. Current guidelines recommend an approach that aims to normalize patients’ lives. The Canadian Physician Hereditary Angioedema Practice Pattern Survey is intended to better understand how physicians in Canada manage HAE patients and if guideline recommendations are followed. The goal of the study is to identify any potential care gaps so the future versions of guidelines can address barriers that might interfere with optimizing care for HAE patients.
This study will be conducted across Canada by reaching out to physicians to treat HAE through the Canadian Hereditary Angioedema Network (CHAEN). The study consists of a survey that physicians will complete, as well as a qualitative interview process, to better understand potential barriers that physicians may face in trying to optimize goals of HAE treatment. This will be the first study that combines both a survey and an interview format to assess physician practice patterns related to HAE patient care.
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This award was jointly funded by the Canadian Allergy, Asthma and Immunology Foundation (CAAIF), Canadian Angioedema Scholarship Program (CASP) and Biocryst Canada.
CAAIF-Miravo Healthcare Research Grant in Upper Airway Allergic Disease
Dr. Chris Carlsten
Effects of common air pollutants on allergic rhinitis: A controlled human exposure study
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Allergic rhinitis (AR) affects 1 in 4 Canadians, with impacts on their well-being and productivity. It is closely linked to asthma, and both conditions are aggravated by air pollution, causing worsened symptoms and reduced quality of life. Traffic-related air pollution (TRAP) and wood smoke (WS) are major contributors to Canada's outdoor air pollution. Diesel exhaust (DE - model of TRAP) and WS are known to have adverse health effects, including respiratory and cardiovascular issues. However, no human studies have compared the harm caused by the two. Our research aims to address this gap, as we cannot assume that WS has the same effects as DE and must form guidance specific to WS.
We will conduct a randomized, double-blinded, crossover trial to examine how DE and WS exposure affects airway function in individuals. This study will look into the impacts of DE and WS on airway function, especially those with allergic rhinitis. Such data is essential amidst growing support, driven by economic and government initiatives, for transitioning diesel generators to wood pellet systems in rural, remote, and indigenous communities. The findings from this research could contribute to developing exacerbation prevention strategies, inform government policies, and shape treatment approaches for rhinitis.
CAAIF-CLA Research Fellowship
Dr. Clarus Leung
Endo-phenotyping of Asthma and Chronic Obstructive Pulmonary Disease Overlap by Airway Inflammation and Structure
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Chronic obstructive pulmonary disease (COPD) and asthma are two different diseases that affect the airways. Around one-third of COPD and asthma patients have features of both asthma and COPD and thus are diagnostically labeled as asthma-COPD overlap (ACO). ACO patients experience worse symptoms and more serious respiratory attacks than those with COPD or asthma alone, but we do not know why. To address these questions, our study will investigate the underlying inflammatory mechanisms in the airways of patients with ACO. We will collect tissue samples and cells from the airways of volunteers with ACO using a technique called bronchoscopy and perform genomics on these samples. These data will enable us to identify the key airway features of ACO. We will also use this cohort to determine which features of ACO lead to a good therapeutic response from inhaled corticosteroids, a class of medications used in COPD and asthma. We will use high-resolution imaging techniques to investigate how inflammation relates to persistent changes in the structure of the airways and the lungs. Our research will reveal the disease mechanisms of ACO so that we can better diagnose and prescribe the most effective therapies for ACO in clinical practice.
This award was jointly funded by the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Lung Association (CLA).
CAAIF-CLA Allied Health Research Grant
Shirley Quach
Does the use of biologics in children with severe asthma improve health outcomes and quality of life? – A longitudinal cohort study
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Asthma is the most common chronic disease in childhood, with about 2 to 5% of children with severe asthma reporting poor quality of life. "Asthma biologics” new injectable medications, may be beneficial in certain groups of children with severe asthma, improving their overall lung health. But asthma biologics is estimated to cost at least $8,000 per patient each year, a heavy price shared amongst patients, their families, and the healthcare system. Past studies focused on the use of asthma biologics in adults, with less attention on children and adolescents.
Health data before and after asthma biologics will be collected, reviewed and compared in children with asthma, aged 12 to 18 years, from 2014 to 2022, from the Hospital of Sick Children’s health database. We will use different statistical tests to see if there are any short- or long-term trends after different asthma biologics.
It is important for healthcare providers and policymakers to understand the cost and benefits of asthma biologics to help guide practices, optimizing their use in children with severe asthma. It will also highlight how asthma biologics impact children and their families, directing future education and research to support their lung health and management.
This award was jointly funded by the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Lung Association (CLA).
Graduate Student Awards in Asthma
Courtney Hoskinson
Data from the CHILD cohort study: functionally linking the early-life gut microbiome to health and disease
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Allergic diseases affect hundreds of millions of children worldwide and continue to increase in prevalence. Many risk factors for allergic diseases, such as antibiotic usage, also influence microbes and their genes within the gut, which, together, are commonly known as the gut microbiome. Maturation of the gut microbiome usually occurs at the same time as the development of healthy immune tolerance. However, if microbiome maturation is abnormal, allergic sensitization can emerge in some children as a result.
My research combines school-age allergic diagnoses with early-life gut microbiome composition, functional capability, and metabolite concentrations for the quantification of a ‘normally’ maturing gut microbiome. This data primarily stems from CHILD (n=3,455), a large Canadian longitudinal study with robust information on participant environment and microbiome. To increase the strength and relevance of my findings, I will not only identify associations in CHILD, but I am also working with my colleagues and collaborators to validate our findings in other populations with clinical and microbiome data, such as the Copenhagen Prospective Study on Asthma in Childhood (COPSAC).
The aims of my research are to (1) identify unifying gut microbiome maturation signatures in asthma, allergic rhinitis, food allergy, and atopic dermatitis, collectively called the ‘Allergic March’, (2) functionally link antibiotic usage to the onset of specific allergic diseases using microbiome data, and (3) connect microbial-dependent influences on participant immune cell profiles to allergy. My investigation of the early-life gut microbiome will thus empower new predictive and preventive strategies to avoid allergic diseases.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Awards in Asthma
Natasha Kuncher
Mapping airway remodelling in asthma using multimodal Raman-Second Harmonic Generation imaging and machine learning
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Asthma is a chronic inflammatory disease, impacting approximately 11% of the Canadian population. Inhaled allergens damage the tissue barrier lining the lungs, leading to the inflammation of airways and difficulties in breathing. To remodel impaired tissue, damaged airways trigger a complex cellular response, denoted by the excessive accumulation of extracellular matrix (ECM) proteins; particularly collagen I. Evidence suggests that this fibrotic response, known as subepithelial fibrosis (SF), contributes to tissue stiffening, airway blockage and an overall reduction in lung function.
With the goal of setting a new precedence for imaging and to better visualize ECM protein deposition at high resolution, our research applies a label-free multimodal imaging system embedded with the technologies of both Raman microspectroscopy and Second Harmonic Generation. This imaging system is the only of its kind in Canada, and is used to develop biochemical maps of tissues and cells while simultaneously detecting signals related to fibrillar collagen. Due to the complex nature of the data obtained, the development of novel approaches based on machine learning (ML) strategies to identify biomarkers associated with asthmatic airway remodelling is necessitated. Using ML, an automated classification pipeline will be developed to characterize spectral signatures unique to the basement membrane, epithelium and lamina propria of airways.
Insight into the fibrotic responses in asthma with an unprecedented level of spatial and biochemical specificity will drive the identification of biomarkers active in disruptive airway remodelling and support therapeutic development minimizing the formation of scar tissue observed through the excessive burden of SF.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Awards in Asthma
Courtney Marshall
Mapping airway remodelling in asthma using multimodal Raman-Second Harmonic Generation imaging and machine learning
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Asthma is the most common chronic respiratory disease affecting nearly 3 million Canadians including children. Around 15% patients do not respond to available steroid therapies and represent the major burden of asthma accounting for annual healthcare costs of $2B. Also, common steroid therapies can increase the risk of lung infections, which can make asthma worse. New therapies are urgently needed that can alleviate steroid-unresponsive disease without compromising the ability to resolve infections.
There is a clear sex bias in asthma, for example adult females experience greater disease severity and are more likely to develop steroid-resistance, compared to males. These sex-related differences are largely ignored during drug development. Effective development of new treatments must consider the differences in disease and response to therapy between females and males.
This study focuses on new molecules known as innate defence regulator (IDR) peptides, which can control both inflammation and infection. We have shown that IDR peptides improve breathing capacity in an animal model of asthma, and control cellular processes linked to steroid unresponsiveness. This project aims to develop IDR peptides as a new therapy for asthma, by examining the effects in both females and males concurrently. This research will directly support the development of a new IDR peptide-based therapy for asthma, by taking into consideration how the treatment affects females compared to males. It is entirely possible that we will need to develop sex-specific treatment protocols to provide the most efficient care for asthma sufferers.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Awards in Asthma
Jo-Chiao Wang
Basophilic oncostatin M fuels nociceptor neuron-induced asthma
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Despite affecting less than 10% of asthmatic patients, severe asthma accounts for 60% of the asthma healthcare cost due to the lack response to corticosteroid treatments. Recent advance of single-cell gene profiling reveals a population of airway sensory neurons expressing similar genes as neurons sensing skin itch. However, molecular and pharmacological characterizations of this population are insufficient. With real-time calcium imaging, we can visualize the calcium influx, a neuronal activation event, in response to different stimulants. We can thus cluster the neurons based on their reactivity to different drugs as well as evaluate neuron’s sensitivity under normal and asthmatic condition.
We have thus far demonstrated that lysophosphatidic acid-responding neurons and serotonin-responding neurons are two distinct populations, which respectively represent jugular and nodose nociceptors in vagal sensory ganglia, from where the airway sensory neurons arise.
We also noticed that some jugular neurons express the receptor of oncostatin M (OSM), a cytokine associated with exaggerated itch sensation in atopic diseases. We then ask if OSM is expressed in asthmatic context and by which cells. With cell sorting and RT-qPCR techniques, we identified lung basophils as the main cellular source of OSM under normal and asthmatic conditions. As it sensitizes itch neurons, OSM can also sensitize vagal sensory neurons, shown by our calcium imaging data.
Whether OSM affects asthmatic pathophysiology through sensitizing airway sensory neurons is yet to be determined. We hope this novel neuroimmunology pathway provides a new possibility in seeking alternatives to glucocorticoid treatment.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).