Dr. Hélène Decaluwe
CAAIF-CSACI INNOVATIVE RESEARCH GRANT IN ALLERGY & CLINICAL IMMUNOLOGY
In vivo Prime Editing of HSC for correction of perforin-deficiency
Familial hemophagocytic lymphohistiocytosis (fHLH) is a life-threatening dysregulation of the inflammatory response caused by genetic defects in the lymphocyte granule-mediated cytotoxic pathway. The only cure for this lethal disease is allogeneic hematopoietic stem cell transplantation (HSCT). The outcomes of HSCT for fHL can vary depending on several factors, including the specific genetic mutation, the control of HLH at the time of transplant, and the quality of the HSCT donor match. Our objective is to develop a gene therapy (GT) approach to treat patients affected by perforin-associated fHLH using systemic nanoparticle-mediated in vivo delivery of a prime editor specifically designed to correct the PRF1 gene, which encodes the perforin protein. We hypothesize that this approach will allow for the correction of PRF1 pathogenic variations directly within the HSC niche. This will enhance all aspects of the current cell therapy strategy targeting HSCs through precise gene correction, the avoidance of HSC collection, and myeloablative conditioning regimens.
Dr. Derek Chu
CAAIF-CSACI INNOVATIVE RESEARCH GRANT IN ALLERGY & CLINICAL IMMUNOLOGY
Skin health and allergen exposure strategy to prevent atopic march: SHAPE pilot trial
Food allergy and eczema affect millions of Canadians. They start early in life and place large burdens on patients, families, and the healthcare system. There are no current preventative therapies for the early-life onset of food allergy and eczema.
Building on previous work such as our contributions to the CHILD cohort study, randomized clinical trials in pregnancy and allergy, and systematic reviews of the evidence, we identified early-life exposures as being highly associated allergy development: excessive early-life bathing, antimicrobial exposure, soap/detergent exposure, and skin environmental exposure to allergens.
For this CAAIF-CSACI Innovative Research Grant in Allergy & Clinical Immunology, The Skin Health and Allergy Prevention Exposure (SHAPE) trial will evaluate the feasibility and effect of a low-cost, parent-delivered multicomponent intervention improving skin barrier integrity, microbiome health, and allergen exposure in early infancy to prevent the development of eczema and food allergy. This study will inform future RCTs. We will learn further about how allergies begin in early in life by analyzing genes and molecules.
Dr. Harissios Vliagoftis
ASTHMA CANADA-CAAIF RESEARCH GRANT IN ASTHMA INNOVATION AND IMPACT
Exploiting microbial allergen metabolism to improve oral immunotherapy safety and outcomes
Asthma affects more than 3 million Canadians. Symptoms of asthma develop as a result of “inflammation”, which is the response of the body to allergens, irritants or microorganisms. Inflammation in asthma is characterized by the presence of a type of immune cells called eosinophils, but many other cell types also contribute. One category of cells called monocytes circulate in the blood and come to the lungs in response to inflammation. Based on data from human, but also animal studies, we propose that monocytes are the first inflammatory cells that come to the lungs when patients with asthma experience increased symptoms. Monocytes then generate factors that attract other inflammatory cells, especially eosinophils. Eosinophils are responsible for the severe chronic symptoms we see in these patients. Our aim with this project is to develop the data we need to support this hypothesis.
If we understand better the role of monocytes in asthma, we may be able to develop approaches to block their accumulation in the lungs to treat asthma. This is very relevant as there are drugs that can prevent accumulation of monocytes that are used to treat other conditions and it is possible to test these drugs in patients with asthma.
Dr. Anne Ellis
ASTHMA CANADA-CAAIF RESEARCH GRANT IN ASTHMA INNOVATION AND IMPACT
TEZepelumab in Allergic Rhinitis and asthma Study (TEZARS): An Open-Label Exploratory Mechanistic Pilot Study to evaluate tezepelumab in allergic rhinitis and asthma
To stop the rise in new cases of food allergies we need to understand factors that contribute to allergy development. In people with food allergies the immune system becomes activated after being exposed to the problem food, causing allergy symptoms. This inappropriate immune activation often begins in infancy, where the system fails to learn not to become active after eating that particular food. In healthy people who do not have allergies a process occurs called ‘oral tolerance’, where after eating different foods, their immune system essentially learns not to mount an allergic reaction to these same foods later in life. Oral tolerance starts to develop early in life, as soon as we get exposed to different foods through breast milk and through the introduction of solid foods. We have learned a lot about the immune cell types involved in oral tolerance development from experimental studies in mice, however, much of this knowledge comes from studies of adult mice, not from young mice. The immune system functions differently in young animals as it is still developing, and exposure to breastmilk impacts cell types involved in oral tolerance.
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One factor that may impact the process of oral tolerance development is exposure to antibiotics: pregnant females in North America are commonly given intravenous antibiotics prior to and during labour (intrapartum antibiotic prophylaxis). We will use model models to investigate whether this type of early life antibiotic exposure impact’s the infant’s ability to develop oral tolerance to food substances during early life.
Dr. Alejandro M. Palma
CAAIF-CASP-KALVISTA RESEARCH GRANT IN HEREDITARY ANGIOEDEMA (HAE)
Exploring Biomarkers for Clinical Heterogeneity in Hereditary Angioedema
Hereditary Angioedema (HAE) is a rare genetic disease characterized by excessive bradykinin production after certain triggers, leading to recurrent swelling episodes and significant morbidity. Clinical manifestations and treatment responses vary widely among patients, but the reasons behind this heterogeneity remain unclear.
This study aims to explore the relationship between bradykinin B2 receptor (B2R) turnover, bradykinin production, and the occurrence of acute HAE attacks. We will assess both surface and total (permeabilized) expression of B2R—and secondarily B1R—on monocytes and other blood cells by flow cytometry using fresh blood from patients and controls. These measurements will serve as indirect indicators of B2R turnover in the absence of acute symptoms, reflecting baseline kinin dynamics.
As secondary endpoints, we will quantify plasma cleaved and intact high-molecular-weight kininogen (HMWK) to evaluate kallikrein-kinin system activation. We will then correlate these biomarkers with clinical features and disease severity.
We hypothesize that B2R expression and cHMWK levels will be globally elevated in patients with severe or refractory HAE phenotypes. Understanding the dynamics of these biomarkers could clarify the biological basis of clinical variability and support future strategies to predict attack risk and personalize prophylactic or therapeutic interventions.
Dr. Jenny Garkaby
CAAIF-IMMUNODEFICIENCY CANADA EARLY CAREER INVESTIGATOR AWARD IN PRIMARY IMMUNODEFICIENCY
Unmasking B Cell Dysfunction in Primary Immunodeficiency: In Vitro Assay for Assessing B Cell Response to Polysaccharide Antigens
The project aims to develop an in vitro assay for assessing T cell–independent polysaccharide-responsive B cell immunity in patients with suspected B cell defects. This initiative responds to the discontinuation of Pneumovax, which previously served as the primary clinical tool for evaluating specific anti-polysaccharide antibody responses post-immunization.
Given the current limitations in available polysaccharide vaccines, and the absence of reliable alternative assays, this project focuses on establishing an accurate, scalable method to quantitatively measure B cell–mediated responses to polysaccharide antigens in vitro. We hope to create a diagnostic platform that enables to identify patients with B cell defects, thereby reducing diagnostic uncertainty and improving patient management.
Dr. Priyanka Pundir
CAAIF RESEARCH GRANT IN ATOPIC DERMATITIS
Defining a New Axis of Microbial-Host Crosstalk in Chronic Skin Inflammation
Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 20% of children and a significant proportion of adults. Current therapies targeting type 2 cytokines such as IL-4 and IL-13 provide only partial and transient benefit, with high rates of relapse upon discontinuation. These limitations highlight the need to better understand the upstream triggers and immune circuits driving disease persistence and recurrence. One poorly defined area involves how the skin's immune system responds to microbial signals, particularly from Staphylococcus aureus, a common colonizer of AD lesions. This project investigates how bacterial peptides secreted by S. aureus initiate immune activation in the skin, leading to inflammation characteristic of AD. Preliminary data from a mouse model show that epicutaneous exposure to S. aureus induces hallmark features of AD, including barrier dysfunction and elevated type 2 cytokines. However, when we disrupted a specific microbial sensing pathway, mice failed to develop skin inflammation despite similar bacterial burdens, suggesting that host recognition of virulence factors, rather than colonization alone, drives disease. Building on this finding, we will dissect the molecular mechanisms through which microbial peptides activate immune responses in the skin and promote downstream inflammation. Using in vivo and ex vivo approaches, we will define the contribution of this microbial sensing axis to antigen presentation, T cell activation, and cytokine release. Our goal is to identify actionable upstream events that could inform future therapeutic strategies targeting inflammation at its source. By uncovering how host–microbe interactions contribute to immune dysregulation in AD, this research will expand our understanding of disease mechanisms and open new avenues for intervention in chronic inflammatory skin disorders.
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This Grant was jointly funded by CAAIF and Inctye Biosciences Canada.
Jenysbel Hernandez Reyes
GRADUATE STUDENT AWARDS IN ASTHMA
Development of a novel, targeted, cell-based immunotherapy for the treatment of asthma
Asthma is a long-term disease that causes inflammation and narrowing of the airways, making it hard to breathe. It affects around 300 million people globally and leads to over 180,000 deaths each year. Current treatments for severe allergic asthma mainly help control symptoms but don’t fix the root cause of the disease. They can also have serious side effects and are not always effective in stopping the disease from getting worse.
This project aims to develop a new, targeted, and long-lasting treatment for severe allergic asthma using a modified form of immune therapy called CAAR-T cells. These specially engineered T cells are designed to find and destroy only the harmful immune cells (IgE-producing B cells) that drive asthma, while leaving the rest of the immune system intact. We will first test these cells in the lab to see if they can effectively kill allergy-causing cells. Then, we will test their safety and effectiveness in mice with asthma. We will compare the efficacy of the treatment when administered before or after the onset of asthma symptoms.
If successful, this approach could lead to a new kind of cell-based therapy that may one day cure severe asthma or prevent it from developing altogether.
This Award was jointly funded by CAAIF and Asthma Canada.
Israel Shpliman
GRADUATE STUDENT AWARDS IN ASTHMA
B-Lymphocyte derived extracellular vesicles as key regulators of allergic airway inflammation
Asthma is a long-term lung condition that affects over 262 million people worldwide, causing significant illness and around 455,000 deaths each year. Our lab is focusing on a type of immune cell called B-lymphocytes, which help regulate inflammation, including in asthma. We’ve discovered that these cells release tiny particles called extracellular vesicles (EVs), which are important for cell-to-cell communication and control of inflammation. These EVs carry proteins, fats, and genetic material (RNA), including microRNAs (miRNAs), which can affect how cells behave. In our research, we found that B2-EVs, a special type of EV produced by B-cells, can help reduce airway inflammation in asthma. We also discovered that certain miRNAs in these B2-EVs are linked to controlling the growth of cells involved in inflammation, such as eosinophils. In the first part of our project, we plan to investigate how specific miRNAs in B2-EVs influence eosinophil development and the inflammation process. By manipulating these miRNAs, we aim to understand which ones are most effective in controlling asthma-related inflammation. In the second part, we’ll test whether we can use these miRNAs as a treatment. We will introduce synthetic miRNAs to eosinophils in lab settings and in animal models to see if they can prevent excessive growth and inflammation. Ultimately, our goal is to find new ways to reduce asthma symptoms and improve treatments.
This Award was jointly funded by CAAIF and Asthma Canada.
Omar Abdelraheem
GRADUATE STUDENT AWARDS IN ASTHMA
Elucidating the development and pathogenicity of dual-positive Th2-Th17 cells
Asthma is a common lung disease that affects about 300 million people worldwide and is associated with wheezing and shortness of breath. It is often caused by immune reactions in the lungs that are driven by immune cells called T-helper cells. Normally, these cells protect the body against threats, like microbes, by activating other immune cells. However, T-helper cells are associated with asthma by mediating inflammation, particularly T-helper 2 (Th2) cells and T-helper 17 (Th17) cells. In many cases, asthma is caused by inflammation from Th2 cells. As it becomes more severe, Th17 cells increase in frequency and cause inflammation alongside Th2 cells. This mixed inflammation has been reported to mainly come from hybrid Th2-Th17 cells. We want to study the processes by which Th2-Th17 cells develop and which of their features worsens asthma. To answer these questions, we will first examine how Th2 cells respond to molecules that we believe may induce them to become Th2-Th17 cells. We will then track what characteristics these cells develop. Our work will help deepen the knowledge of how different types of Th2 cells play a role in asthma. Understanding if and how Th2-Th17 cells increase asthma severity could uncover clues about new therapies that can be created to treat severe asthma patients.
This Award was jointly funded by CAAIF and Asthma Canada.
Oscar Gonzalez-Morales
GRADUATE STUDENT AWARDS IN ASTHMA
Effect of cationic host defense peptides on Histone Deacetylase 2 (HDAC2) and related pathways, in steroid-unresponsive asthma.
Asthma causes lung inflammation and narrowing of the airways making it difficult to breathe. It is the most common chronic respiratory disease affecting more than 4.5 million Canadians. This disease lowers the quality of life and costs the Canadian economy more than $2 billion each year. Approximately 10-15% of asthma patients do not respond to available steroid treatments and suffer from steroid-resistant (SR) severe asthma, representing more than 50% of the asthma-related healthcare burden. Therefore, new treatments are needed for SR severe asthma.
This study focuses on understanding biological processes that can be targeted to control SR asthma, by using molecules known as Innate Defence Regulator (IDR) peptides. We showed that an IDR peptide controls lung inflammation, improves breathing capacity, and intervenes in cellular processes linked to SR asthma. A protein that is decreased in the lungs in SR asthma is HDAC2. This project will examine how IDR peptides restore the levels of this protein in the lungs and consequently decrease lung inflammation related to SR asthma.
The findings from this project will identify cellular targets that can be used to control SR asthma, as well as establish the use of IDR peptides as a new therapeutic approach. Additionally, this project will advance the knowledge required to develop new strategies to control SR severe asthma, for which there are no available treatments.
This Award was jointly funded by CAAIF and Asthma Canada.