In that effort, LJI Professor Pandurangan Vijayanand, M.D., Ph.D., recently applied next-generation computational approaches to take a global snapshot of gene expression in both Th1 and Th2 cells. To do so, he surveyed the entire genome of both asthmatic and control non-asthmatic individuals for short stretches of DNA called enhancers, which switch target genes on and off. This analysis, conducted with LJI Professors Bjoern Peters, Ph.D., and Anjana Rao, Ph.D., identified a manageable number of genes inappropriately switched on in Th2 cells of asthmatic patients, factors that could potentially serve as novel therapeutic targets.
T helper signaling whips up the inflammation that drives asthmatic attacks. But the cellular perpetrators are mast cells, which release the histamine actually provokes physiological symptoms. A few years ago, LJI Professor Toshiaki Kawakami, M.D., Ph.D., discovered that a proinflammatory protein called histamine-releasing factor (HRF) activated a receptor expressed on mast cells, causing them to release histamine. Since then, his lab has identified two peptides that can block HRF activity and decrease airway inflammation in mouse models of asthma, discoveries could lead to similar approaches in patients.
In the lab of LJI Associate Professor Ferhat Ay, Ph.D., researchers are using advanced bioinformatics tools to analyze immune cell data to find any asthma-specific biomarkers. This work, a collaboration with the Vijayanand Lab, may shed light on why some people are more vulnerable to severe asthma than others, and why life-saving therapies don’t work for all patients.
Turning off LIGHT
LJI Professor Michael Croft, Ph.D., is applying his expertise in autoimmune disease to counteract airway wall thickening and tissue scarring, known as fibrosis, seen in asthmatic patients. Croft found that activity of a pro-inflammatory factor called LIGHT increases airway wall thickness and perturbs lung function in asthma. LIGHT is a member of the TNF protein family, factors strongly implicated in autoimmunity. His lab has since discovered that when asthma model mice were treated with drugs that block LIGHT, mice showed less airway fibrosis after allergen exposure.
Croft is developing the idea that LIGHT inhibitors may be effective in reversing tissue destructive effects of fibrosis not only in asthmatic lung but in chronic obstructive pulmonary disease (COPD) or skin diseases like scleroderma or eczema. Drugs targeting LIGHT are now in safety trials and could be used in the future in patients with fibrosis.
Croft’s research also led to the discovery in 2020 that blocking two immune molecules at the same time is key to preventing asthma attacks in a mouse model. Croft and his colleagues worked with a mouse model sensitive to house dust mites—a very common allergy and asthma trigger. The scientists showed that blocking OX40L and CD30L at the same time could stop the expansion and accumulation of harmful T cells in the lungs during an allergen attack, and this then led to reduced inflammation.
Hypoxia is a brief period where a person cannot breathe properly. Experiencing hypoxia is a known trigger for developing and worsening lung conditions such as severe asthma, chronic obstructive pulmonary disease (COPD), and fibrosis. To treat and prevent these diseases, researchers need to understand why a lack of oxygen would affect the immune system. In a 2022 study, LJI Professor Mitchell Kronenberg, Ph.D., showed that hypoxia can activate the same group of immune cells that cause inflammation during asthma attacks. As a person with gasps for breath, these cells flood the airways with molecules that damage the lungs, paving the way for long-term lung damage. The research team also showed that human lung epithelial cells exposed to hypoxia produce a molecule called ADM. This means ADM or its receptor could be targets for treating inflammatory and allergic lung diseases.