Findings May Improve Clinical Trial Design for Experimental Therapies
A new study has shown that targeting two immune cells—Th2 and Th17—and their downstream, inflammatory effects is better than targeting just one pathway in the context of asthma. The researchers also show that blocking the Th2 pathway, which is a target of commonly-prescribed corticosteroid drugs, may unexpectedly boost conditions for Th17-driven inflammation. These results clarify how immune cells and their products contribute to asthma, and the work may enable researchers to design and test therapies that target both pathways. The study appears in the August 19, 2015, edition of Science Translational Medicine and included scientists from NIAID, the University of Leicester, and Genentech.
Asthma Subtypes Lend Clue
Asthma affects the airways of the lungs, resulting in breathing difficulties, coughing, wheezing, and chest pain. Environmental triggers, such as pollen, mold, and viruses, cause inflammation and constrict the airways, resulting in an asthma attack. Researchers are studying why and how airways become inflamed, which occurs when the immune system overreacts.
Although people with asthma share similar symptoms, scientists are looking more closely at how patients differ, subgrouping based on the types of aberrant immune signals observed. Approximately 10 percent of people with asthma do not achieve disease control under conventional therapies and may benefit from more targeted therapies that address the specific immune problem.
In the new study, the researchers looked retrospectively at lung samples from 51 asthma patients who had a range of disease severity. The team found that the patients clustered into three groups based on the activity of immune cells associated with asthma—Th2 and Th17. Patients exhibited high Th2, high Th17, or low activity of both pathways. Interestingly, no patients had simultaneously high Th2 and Th17 activity, indicating that these pathways are somehow mutually exclusive.
Immune Cells Drive Inflammation
Th2 cells and their products, including signals called interleukin 4 (IL-4) and interleukin 13 (IL-13), are known drivers of asthma. Corticosteroids, which are prescribed for treating asthma attacks, lower Th2 activity, among other effects. More recently, Th17 cells and their products, including interleukin 17 (IL-17), have attracted more attention as researchers uncovered their role in inflammatory diseases. However, how these pathways influence each other is less known, particularly in the context of asthma.
The study team used a mouse model of asthma to explore Th2 and Th17 activity, and they tested the effect of blocking Th2 activity alone or blocking both Th2 and Th17. Interestingly, mice that receive anti-Th2 therapy, which suppressed IL-4 and IL-13 signals, experienced enhanced Th17 responses. The findings suggest that Th2 may serve as a brake for Th17. When Th2 is blocked, conditions are unexpectedly primed for Th17 activity, which may influence the effectiveness of therapy over time. In line with this idea, the patients who exhibited high Th17 activity were all taking corticosteroids, with moderate to severe disease.
When Th2 and Th17 were simultaneously blocked in the mouse model of asthma, the researchers observed greater benefit than blocking one pathway alone. Dual treatment resulted in less airway inflammation, less mucus production, and importantly, no enhancement of Th17 activity; Th17 activity typically is associated with inflammation caused by neutrophils, a type of immune cell. The study highlights the need to explore both inflammatory pathways in asthma research.
NIAID researchers are further assessing the benefits of simultaneously targeting the Th2 and Th17 pathways. Potentially, designing a clinical trial that addresses both pathways may yield more benefit than previous trials that only addressed one pathway. Overall, gaining a better understanding of how these immune pathways cross-regulate in people will advance therapeutic research for asthma and other inflammatory diseases.
Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, Butler CA, Hargadon B, Sciurba JC, Gieseck RL, Thompson RW, White S, Abbas AR, Jackman J, Wu LC, Egen JG, Heaney LG, Ramalingam TR, Arron JR, Wynn TA, Bradding P. Th2 and Th17 inflammatory pathways are reciprocally regulated in asthma. Science Translational Medicine (2015).