In that effort, LJI scientist 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’s 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 researcher 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.
Turning off LIGHT
Finally, LJI immunologist 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.