Asthma, Allergy, and Immunology Research Update – May 2020

Platts-Mills Lab

Platts-Mills LabCore team members in Dr. Thomas A.E. Platts-Mills’ lab include Jeffrey Wilson, MD, PhD, Behnam Keshavarz, PhD and Lisa Workman, BA. Working as a team, a major of area of research in the Platts-Mills lab relates to the tick-acquired mammalian meat allergy, often referred to as the ‘α-Gal syndrome’. Since the initial description of the syndrome a little over 10 years ago, the lab has continued to play an important role in increasing our understanding of the pathophysiology and manifestations of the syndrome. Current interests relate to emerging evidence that IgE sensitization to the relevant carbohydrate allergen – galactose-α-1,3-galactose (α-Gal) – could have implications for disorders that are not traditionally considered to be ‘allergic diseases’. To pursue the hypothesis that α-Gal could be relevant to heart disease we are collaborating with Coleen McNamara, MD and Angela Taylor, MD, MPH in cardiology, Robert Hawkins, MD in Cardiothoracic surgery and also Ani Manichaikul, PhD in the School of Public Health Sciences. A major new interest relates to the possibility that α-Gal could be an important cause of IBS-like symptoms among subjects who live in areas where the lone star tick is endemic. To better understand risk factors for α-Gal sensitization we are collaborating with Cade Nylund, PhD at the Uniformed Services University of the Health Sciences in DoD-funded research to assess sensitization incidence among military recruits. We are also working closely with Phil Cooper, PhD to study α-Gal sensitization in a cohort of children in rural Ecuador who live an area that is largely still pre-industrial. The group also has ongoing interests in the nature of antibody responses to common food and aero-allergens, such as cow’s milk and dust mite, with a specific focus on how these responses differ among different populations. Striking differences that are seen between children living in pre- and post-industrial societies likely have implications for thinking about the factors that have contributed to the rise of allergic diseases. The group has several recent publications and is currently funded by an NIH R-37 and R-21 grant. In addition, Dr. Wilson was recently awarded an AAAAI Faculty Development Award for work related to the α-Gal syndrome.

Borish Lab

Dr Larry Borish’s laboratory’s primary focus remains the role of rhinovirus in precipitating asthma exacerbations. These NIH funded studies include an RO1 designed to define the role of an innate immune responses, including anti-viral and T2-promoting immune responses, by infected airway epithelial cells as they might distinguish the consequences of RV infections in asthmatics and healthy control subjects. These studies are further supported by an R21 that will investigate evidences for nascent type 2 inflammation in the lungs of pre-school children with problematic wheeze undergoing clinically-indicated bronchoscopies in whom rhinovirus (RV) infection is identified. In addition, for the next 2½ yrs, the Borish laboratory will be the co-lead sponsor of a Regeneron-funded investigator-initiated study entitled “Viral infection in asthma (VIA) Study: A randomized, placebo-controlled study to assess cellular and molecular markers related to experimental rhinovirus infection in mild asthmatics, and the effect of dupilumab in this investigational model.” The goal of this study will be to assess the molecular and cellular basis by which dupilumab prevents the development of an RV-induced asthma exacerbation. Unrelated to the RV studies, the Borish lab continues to collaborate closely with Dr. Gerry Teague in pediatrics as co-PI for the UVA commitment to the NHLBI funded PreCISE Asthma Network Clinical Centers. These are studies that will enroll severe treatment-resistant asthmatics and investigate novel therapeutics in this refractory population. Finally, we also have several investigator-initiated pharmaceutical studies. Currently, we are enrolling patients in a GSK sponsored study to investigate type 2 inflammation in COPD and more specifically the expression of IL-5 receptor on airway neutrophils. And, lastly, we are supported by a Genentech funded investigator-initiated award involving the presence of type 2 inflammation in cystic fibrosis and the safety and efficacy of omalizumab in that population.

Woolfolk Lab

The overarching objective of current work is to understand immune mechanisms that drive chronic inflammatory processes in the lungs of patients with asthma and to identify mitigating strategies. Rhinovirus (RV) is a major trigger of asthma exacerbations. Ongoing work applies systems biology methods to analyze the immune response to RV in health and disease in human experimental infection models. Our findings support the view that pathogenic Th1 cells targeting RV, are pivotal to promoting and maintaining allergic asthma, even in the absence of infection (Muehling et al., 2016, 2018, and 2020; Wisniewski, Muehling et al, 2018). This shifts the spotlight away from Th2 cells and raises new questions regarding the persistence of viral antigens, and the systemic nature of RV infection. We are forging collaborations with scientists in the Division of Pulmonary and Critical Care Medicine to explore whether RV-specific T cells can contribute to lung pathology in a variety of other disease states. In other work, we have identified a key role for T-bet+ B cells that can bind different RV strains, in the secretion of cross-reactive IgG at the site of RV infection (Eccles et al, 2020). We are currently using a novel model that involves challenging healthy subjects with 2 distinct RV strains, in order to better understand how components of the adaptive response link to cross-protective immunity. Through an inter-disciplinary network of collaborators, we are developing single-cell and integrative analytical pipelines that can build a comprehensive picture of the immune response to RV. The ultimate goals are to inform the rational design of vaccines for RV infection in at-risk populations and to provide tools for immune monitoring in broader disease settings. Work in the Woodfolk lab is supported by U01, R01, and R21 grants from NIH/NIAID.

McGowan Lab

Dr McGowan’s group continues to expand their research on an emerging form of food allergy, eosinophilic esophagitis (EoE). Through her NIH/NIAID K23 Award, Dr. McGowan established the UVA EoE Cohort with her collaborators Drs. Bryan Sauer (Adult Gastroenterology) and Barrett Barnes (Pediatric Gastroenterology). This cohort longitudinally follows approximately 300 patients, and it was designed to examine the environmental, nutritional, and immunologic drivers of this disease. In addition, Dr McGowan recently received a NIH/NIAID R21 Award to examine non-IgE mediated activation of mast cells via food-derived peptides and the role of this pathway in EoE. In a recently funded American College of Gastroenterology award, she and her fellow PI, Dr. Bryan Sauer, are working to better understand the role of dietary triggers in the pathogenesis of EoE. Her group is also collaborating with Dr. Irving Allen (Virginia Tech School of Veterinary Medicine), through a recently funded iTHRIV pilot grant (NIH/NCATS) to investigate the role of the non-canonical NF-kB pathway in the pathogenesis of this disease. Finally, UVA is now a site for the international, multi-center Phase III trial of Dupilumab in treating Eosinophilic Esophagitis (R668-EE-1774).

Lawrence Lab

Dr Monica Lawrence is working with Dr W. Gerald Teague in Pediatrics, Dr Caitlin Welch (Pulmonary/Critical Care fellow) and Dr Larry Borish to continue studies on the expression of the IL-5 receptor on lung neutrophils of children with severe treatment-refractory asthma, with the support of the Allergic Respiratory Diseases Award from the American Lung Association and the American Academy of Asthma, Allergy, and Immunology. Along with Dr. Borish and Allergy/Immunology fellow Dr. Matthew Straesser, she is also researching the role of a low IgE as a sentinel biomarker for evolving humoral immunodeficiency (research sponsored by the Jeffrey Modell Foundation and CSL Behring).

Filed Under: Basic Research, Clinical Research, News and Notes

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