Three MedImmune studies discover hidden role of immune system in COPD and lupus, may lead to the discovery of new treatment options
April 25th, 2016 – MedImmune, the global biologics research and development arm of AstraZeneca, today announced that it has achieved a significant scientific milestone by publishing three manuscripts in Nature Immunology that advance the understanding of the immune system and highlight underlying mechanisms in two little-understood disease areas – chronic obstructive pulmonary disease (COPD) and systemic lupus erythematosus (SLE). These include:
1. The Immune System and COPD: “Inflammatory triggers associated with COPD exacerbations orchestrate ILC2 plasticity in the lung”
o Researchers found that tissue-protective Group 2 Innate Lymphoid Cells (ILC2s) in the lungs of mice changed and acquired physical characteristics similar to inflammatory ILC1s when exposed to cigarette smoke and/or infection in the presence of two key inflammatory signals: Interleukin (IL)-12 and IL-18.
2. The Immune System and ILCs: “IL-1 is a critical regulator of Group 2 Innate Lymphoid Cell function and plasticity”
o Researchers found that the IL-1 cytokine provides signals that cause ILC2s to significantly increase in number and mature into fully functional cells.
3. The Immune System and lupus: “Self-reactive IgE exacerbates interferon responses associated with autoimmunity”
o Researchers found that 54.4 percent of lupus patients studied had DNA-specific IgE, and that this self-reacting antibody contributes to autoimmunity by triggering the secretion of IFN-a, a central inflammatory mediator of lupus pathogenesis.
“At MedImmune, we put great emphasis on science and understanding the pathophysiology of disease,” said Bahija Jallal, Executive Vice President, MedImmune. “The novel findings presented in Nature Immunology challenge the status quo, further our understanding of COPD and lupus, and most importantly, will help increase the scientific community’s understanding of the immune system. Hopefully this will bring us one step closer to developing more effective treatments for patients in the future.”
The Immune System and COPD
Published today, “Inflammatory triggers associated with COPD exacerbations orchestrate ILC2 plasticity in the lung,” researchers studied the way that a type of immune cell known as ILC2 changes when exposed to stimuli such as cigarette smoke and/or infection. Previous research had indicated that smoking alters the immune system’s activity in the lungs, and has noticeable effects that seem to skew the activity of ILC2s. Study highlights:
- Researchers found that tissue-protective ILC2s in the lungs of mice changed and acquired physical characteristics similar to inflammatory ILC1s when exposed to cigarette smoke and/or infection in the presence of two key inflammatory signals: IL-12 and IL-18.
- The same activity may be occurring in COPD, as those patients with a higher ratio of circulating ILC1s in blood had more severe disease and a higher number of exacerbations in the year prior.
- The findings suggest that changes in circulating ILC populations may predict patients at risk and that it may be possible to treat COPD exacerbations by manipulating the switch of ILC1s back into ILC2s.
“Our research shows how versatile and adaptive the immune system can be,” said Alison Humbles, Ph.D., Principal Scientist, MedImmune. “By simply converting one into another, the immune system can switch between ILC2-associated tissue protection and ILC1-driven inflammation. This research is a significant step toward understanding the pathogenesis of chronic diseases like COPD and can guide future therapeutic strategies.”
The Immune System and ILCs
Also published today, “IL-1 is a critical regulator of Group 2 Innate Lymphoid Cell function and plasticity,” researchers provided further mechanistic insights into how the switch between ILC1s and ILC2s is regulated in human cells. This study shows that the adaptability (or “plasticity”) of ILC2s is mediated by a kind of master switch known as IL-1. Study highlights:
- Researchers found that the IL-1 cytokine provides signals that cause ILC2s to significantly increase in number and mature into fully functional cells. IL-1 can also stimulate changes in ILC2s that allow them to be transformed into ILC1s when simultaneously exposed to IL-12 – a kind of cytokine produced during inflammation.
- This study also highlighted IL-1 as an upstream regulator of another set of signals, epithelial cell-derived cytokines (IL-33, IL-25 and TSLP), which are considered primary activators of ILC2s.
- This raises the possibility of another cellular pathway/circuit which regulate ILC2s’ function other than epithelial cells.
“This research opens an entirely new line of investigation into ILC2s,” said Yoichiro Ohne, Ph.D., Scientist, MedImmune. “We now know more about ILC2s, how their activity and plasticity are regulated and key triggers, which gives us multiple options in targeting their activity in situations where we think they’re driving disease. This is an important step in the search for potential therapeutics that can restrain inflammation cycles that are excessive and damaging, such as in COPD.”
The Immune System and Lupus (SLE)
In another Nature Immunology article published in the February 2016 issue, “Self-reactive IgE exacerbates interferon responses associated with autoimmunity,” researchers showed that IgE – an antibody most commonly known to target allergens and produce the histamine response in people with allergies – can also malfunction and target the body’s own DNA. This triggers pathogenic secretion of an immune system activator molecule called IFN-a, which ultimately causes the tissue damage associated with lupus. Study highlights:
- Researchers found that 54.4 percent of lupus patients studied had DNA-specific IgE, and that this self-reacting antibody contributes to autoimmunity by triggering the secretion of IFN-a, a central inflammatory mediator of lupus pathogenesis.
- Accordingly, a correlation between the concentration of DNA-specific IgE in the blood and degree of disease severity was also found.
- The research suggests that DNA-specific IgE may be useful in gauging the effectiveness of lupus treatments. It may also be a useful therapeutic target.
“This research has led to a groundbreaking discovery that IgE leads a double life as a trigger of allergy symptoms and a self-destructive agent in SLE. These findings could have tremendous implications for the lupus community,” said Miguel Sanjuan, Ph.D., Researcher, MedImmune. “In addition to the potential of targeting IgE in lupus patients, these findings show the scientific research community that there is a new realm of previously unknown activity of IgE that unleashes its pathogenic potential beyond orchestrating allergy symptoms, which may also be responsible for other autoimmune conditions.”
MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across key therapeutic areas, including respiratory, inflammation and autoimmunity; cardiovascular and metabolic disease; oncology; neuroscience; and infection and vaccines. The MedImmune headquarters is located in Gaithersburg, MD, and is one of AstraZeneca’s three global R&D centers, with additional sites in Cambridge, UK and Mountain View, CA. For more information, please visit www.medimmune.com.