The goal of the proposed research is to study how two distinct clinical interventions (peptide immunotherapy and bronchial allergen challenge) modulate the phenotype and function of allergen-specific T cells. We will use unique MHC class II tetramer reagents to track, isolate and characterize Fel d 1-specific T cells, before and after the intervention. I am a basic immunologist with a strong history of translational research at the basic clinical interface. For the last 16 years of my career I have focused on gaining an improved understanding of the biology of allergen-specific T cells in two specific clinical models; peptide immunotherapy and allergeninduced asthma exacerbation. My studies were the first to document allergen T cell epitope (peptide)-induced late asthmatic reactions, which can be thought of as “T cell-induced asthma”. These studies identify direct contributions of allergen-specific T cells to symptoms of asthma. I have become a global leader in the development of T cell epitope-based immunotherapy in allergic disease. In order to secure adequate funding for the clinical development of these vaccines, I co-founded a university spin-out company (Circassia Ltd., founded in 1998) that has now raised more than $159million for this purpose and now has vaccines for cat, ragweed, house dust mite and grass allergens in Phase II and shortly Phase III clinical trials. I have invested considerable time in the last 4 years in establishing Canadian company (Adiga Life Sciences) which is a joint venture between McMaster University and Circassia Ltd. Again the purpose of this company is to advance the clinical development of peptide vaccines to clinical practice; in other words, to take the combined knowledge in the field and translate it into improved patient outcomes and a better understanding of the underlying science. I have designed, executed and published 10 studies of peptide administration to human allergic subjects and have been involved in the design of a further 5 unpublished, but completed, clinical trials (sponsored by Circassia Ltd), 2 further ongoing clinical trials and 2 further trials that will have begun by the time this proposal is reviewed. Thus, despite a hiatus induced by moving from the UK to Canada in 2006, I have been productive (in a variety of ways including publications, 5 published patents in the last 3 years, 2 companies, clinical development/trials etc.) over the last 16 years in this area. Establishing Circassia and Adiga Life Sciences, together with my past high level administrative roles in the European Academy of Allergy & Clinical Immunology (EAACI) have given me the expertise and experience to lead the proposed Allergen Epitope Research and Validation Center. To create this exciting opportunity, I have assembled global leaders in their respective fields; Dr. Paul O’Byrne-bronchial allergen challenge models and clinical trials of asthma medications; Dr. William (Bill) Kwok-MHC class II tetramers. We are bringing on capable mid and early-career scientists and clinician scientists to take key roles in the Center, thereby challenging them and advancing their careers. I believe that the demonstrated expertise of our team and the unique clinical models that we can offer, provide an unparalleled opportunity to meet the research objectives and scope of RFA-AI-11-013.
My research experience in the field of allergic asthma and particularly in mouse models of asthma makes me an appropriate investigator for the project “Allergen Epitope Research and Validation Center”. My graduate training was in respiratory physiology and I continue to be interested in the pathologic mechanisms underlying functional respiratory abnormalities. My post-doctoral research training was in the laboratory of Dr. Paul O’Byrne, a team member on this project. During this training I was involved in many clinical trials of asthmatic patients. I continue to be involved in clinical research in asthma, which is invaluable in guiding the basic projects undertaken in my laboratory.
The major focus of my research career has been in the development and application of in vivo models of allergic asthma. Over the past 12 years, we have published extensively using models of brief or chronic exposure to ovalbumin or house dust mite. These models were designed to reproduce aspects of the disease that were missing from existing models. With these models, we have been successful at reproducing several indices of airway wall remodeling and sustained airway hyperresponsiveness. This has allowed us to address questions relating to the mechanisms and pharmacology of these features of asthma.
The studies proposed in the current application have arisen directly as a result of Dr. Mark Larché joining the research team at McMaster University. In our shared laboratory, we have developed in vivo models of exposure to several allergens, including house dust mite, cat and ragweed. These models form the basis of all of the studies in this proposal. The studies address questions about the selection of appropriate peptides for use in human research and for clinical application, as well as basic questions concerning the mechanisms underlying peptide therapy.
The goal of the proposed research is to investigate the mechanisms of allergic airway inflammation, with a particular focus on allergic asthma. Regulation of cell recruitment and activation in the airways is studied in my laboratory using allergen inhalation challenges of mild asthmatic subjects, and cells collected from the airways, peripheral blood and bone marrow. The six papers first-author publications from my doctoral studies describe the kinetics, repeatability, and pharmacological modulation of allergen-induced airway inflammation in human subjects with allergic asthma. These studies show that allergen inhalation challenge induces a repeatable pattern of airway inflammation, which is sensitive to the anti-inflammatory effects of inhaled glucocorticosteroid, and to the pro-inflammatory effects of treatment with regular beta2-agonist. These papers were highly cited, and provide a framework for subsequent studies utilizing allergen challenge to assess the anti-inflammatory effects of other asthma therapies in use, and in clinical development. My objective is to establish a leading research program aimed at delineating the mechanisms controlling the allergen-induced inflammatory response in order to assess anti-inflammatory properties of experimental therapies, and to identify novel therapeutic targets. Collaborations with academic and industry partners is critical to achieving these goals. I collaborate with investigators from the Universities of BC, Alberta, Toronto and others for sharing of protocols and biological samples. I also collaborate with Pharma to pioneer methodology for biological outcomes, including measurements of qPCR on airway-derived cells, development of ELISA-based and progenitor cell assays, and detection of select cells and proteins by flow cytometry. My previous experiences have enforced the need for strong teamwork working towards a realistic research plan, timeline, and budget. The current application builds on my prior work while Dr. Mark Larché will provide expertise in MHC tetramers containing T cell epitopes. My past research and expertise have prepared me to lead the proposed project.
My training in basic and clinical research makes me an appropriate investigator for the project “Allergen Epitope Research and Validation Center”. I have extensive experience in utilizing allergen challenge in human subjects to investigate the mechanisms of allergen-induced inflammation. My PhD thesis developed the nasal allergen challenge in human subjects as a tool for studying allergic inflammation. This involved the study of both cellular and inflammatory mediator responses to allergen challenge. I also gained extensive experience of clinical trial conduct and testing of new therapeutic entities. At McMaster University I have established a research program to study the interaction between upper and lower airway inflammation in allergic disease, with a particular focus on the pathways involved. I have secured peer-reviewed funding to establish my research program. I am an AllerGen NCE Inc. Network Investigator. I am a Co-Director of the Allergic Rhinitis Clinical Investigator Collaborative, a Canada wide network set up to investigate inflammatory, genomic and metabolomic changes following allergen challenge, and effect of therapy on these parameters. I am also currently conducting a trial of a new therapeutic entity targeting eosinophil trafficking. I am also a competent bronchoscopist, and have utilized bronchoscopy in a research setting. I have extensive training in Respiratory and General Internal Medicine which I consider to be very important to ensure the safety of subjects participating in research trials. I am also very aware of the need to conduct trials according to Good Clinical Practice and ICH guidelines.
The study in the current application will utilize my expertise in clinical trial conduct in the field of allergy in human subjects to evaluate the mechanisms of peptide immunotherapy against cat allergen. The current application builds on this expertise, with Dr. Mark Larché providing his expertise in MHC tetramers containing T cell epitopes.
My training in basic and translational research makes me an appropriate investigator for the project “Allergen Epitope Research and Validation Center”. I have very extensive experience in utilizing allergen inhalation challenge, both in animal models and in human subjects to investigate the mechanisms of allergen-induced airway responses, allergen-induced regulation of inflammatory cell production in the bone marrow, the recruitment of inflammatory cells into the airways, the release of inflammatory mediators, and the consequences of this mediator release on airway function. These studies have included studies on the trafficking of eosinophils, dendritic cells and T-cells, the release of eicosanoids and inflammatory cytokines and the effects of this on airway remodeling and the functional consequences, expressed as allergen-induced late responses and airway hyperresponsiveness. My laboratory also has experience in conducting clinical trials of potential new therapies for allergic asthma, using inhaled allergen challenge in asthmatic subjects. These potential therapies included a disaccharide derivative of heparin, which has anti-inflammatory properties; two different humanized monoclonal antibodies (hMab) against IL-13; hMabs against activated complement (C5a), OX40 ligand, IL-9; anti-sense against IL-4R; and, a CXCR2 antagonist, and inhaled anti-sense against the common β-chain for the cytokines IL-3, IL-5 and GM-CSF, as well as against the chemokine receptor CCR-3. We have published more that 80 peer-reviewed papers on the mechanisms and treatment of allergen-induced airway responses alone. The study in the current application will utilize our expertise in allergen inhalation challenge in human subjects to evaluate the mechanisms of peptide immunotherapy against cat allergen. My previous research experiences have included extensive collaborations with investigators across the world, as reflected in my publication list. The studies of new treatments for asthma have required a research team that is focused and effective, with realistic research plans, timelines, and budgets. The current application builds on this expertise, with Dr. Mark Larche providing his expertise in MHC tetramers containing T cell epitopes.
My laboratory has been using class II tetramers to interrogate antigen specific CD4+ T cell responses for more than ten years. I am one of the pioneers in developing class II tetramer reagents and have published more than 50 articles in this area of research, including recent work with allergen specific CD4+ T cells. My laboratory was awarded an NIH contract in 2007 to utilize tetramers to identify allergen specific CD4+ Tcell epitopes, including T cell epitopes from cat dander. Thus, my laboratory has extensive experience working with blood samples from allergic subjects. Recently, we established a standard protocol for phenotyping antigen specific CD4+ T cells by staining and analyzing PBMC ex vivo with tetramers. Currently, my laboratory routinely uses 12 color flow cytometry to define the phenotype of allergen specific CD4+ T cells. Thus I am qualified to carry out the research as proposed.
Tom works in Dr. Mark Larché’s lab as a project scientist. He has strong work experience in immunology and molecular biology research fields. He is expert in flow cytometry and molecular cloning techniques. He has been trained by BD bioscience to operate FACSAria III sorting machine. His research interests focus on the studies of mechanism of allergy immunotherapy with clinical trials samples. His research contributes to the developments of vaccines for immunology diseases.
Lesley is a Research Assistant in the Larche Lab. She completed her BSc is Biochemistry at McMaster and has been working for the University ever since. Her work in the lab mainly focuses on the various ongoing allergy studies.
Cheryl is a Lab Technician in the Larché lab. She completed her BSc at the University of Toronto and joined the Larché Lab after moving to Hamilton. Cheryl works on most of the allergy studies in the lab, as well as helping students with their research projects.
Jennifer is a research technician in Dr. Gauvreau's lab. Outside of the lab Jennifer works a few shifts a month at an emergency veterinary clinic. Jennifer has an adorable 6 year old son, and they like to bicycle, hike with the dog, and go to the movies.
John-Paul is interested in pursuing research as a career. Currently a graduate student of Dr. Gail Gauvreau at McMaster University studying B cell biology and the pathobiology of allergic asthma. Affiliated with the Hospital for Sick Children as a research assistant in the Department of Emergency Medicine.
Dr. Antje Ask received her medical degree at the University of Wuerzburg, Germany, and completed two years of residency training in Internal Medicine before moving to Hamilton for a post-doctoral research fellowship at McMaster University. Her main research focus during this fellowship was the pathobiology of chronic lung diseases, in particular Idiopathic Pulmonary Fibrosis. During that time, Dr. Ask was also working clinically in the Firestone Institute for Respiratory Health (FIRH), enhancing her interest for translational science by linking clinical manifestation of chronic lung diseases with research studies investigating potential contributors to the development of disease. After a second research fellowship at the National Heart Lung and Blood Institute, National Institutes of Health, studying the causes of pulmonary hypertension in sickle cell disease, Dr. Ask returned to McMaster University. She has since established and is currently managing the Pulmonary Research Registry (PURR), a database designed to facilitate patient recruitment for various research studies at the FIRH. In her present role as “Clinical Research Liaison”, Dr. Ask is focusing on streamlining patient enrollment for research studies, public outreach and education, and strengthening of clinical and scientific collaborations.