Eczema is usually treated by suppressing the immune system, but the aggravating skin condition may also be controlled by boosting selected immune functions. Specifically, eczema may be ameliorated by boosting immune cells known as natural killer (NK) cells.
This counterintuitive finding emerged from an analysis of blood samples taken from 25 eczema patients and 363 controls. When these samples were subjected to multidimensional protein and RNA profiling, deficiencies in certain subsets of NK cells emerged. Most obviously, these NK cells weren’t as numerous in the samples taken from eczema patients. More interestingly, it was found that the cells were likely to follow the activation-induced cell death pathway.
The unexpected link between eczema and NK cells was uncovered by scientists based at the Washington School of Medicine. The scientists, led by Brian S. Kim, MD, a dermatologist and an associate professor of medicine, also demonstrated that circulating NK cells were decreased in a mouse model of eczema. When the scientists used an NK cell–boosting interleukin-15 (IL-15) superagonist, they observed marked improvement in eczema-like disease in mice.
“If you look at the skin of the mice we studied, their eczema resolves in a way we haven’t seen before with other therapies,” said Kim. “And so far, our mouse model of eczema has accurately predicted what we will see in patients.”
Detailed findings appeared February 26 in Science Translational Medicine, in an article titled, “Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis.” The article’s authors noted that eczema treatments usually involve either broad or targeted immunosuppression. Eczema treatments that would enhance the immune system have yet to be tested.
“We demonstrate that patients with atopic dermatitis harbor a blood NK cell deficiency that both has diagnostic value and improves with therapy,” the article’s authors wrote. “Murine NK cell deficiency was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role in this context.”
The authors added that the response they elicited by boosting NK cells in their mouse model reveals a previously unrecognized application of IL-15 superagonism as an immunotherapeutic strategy for eczema. This approach is currently in development for cancer immunotherapy.
At least 10% of the U.S. population has eczema, an itchy, blotchy rash that leaves many patients discouraged due to a lack of many effective treatments. Therapies for eczema include topical steroids, drugs called calcineurin inhibitors, and the monoclonal antibody drug dupilumab (Dupixent), all of which treat the rash by blocking part of the body’s immune response.
Dupilumab, for example, is an immunosuppressant that modulates signaling of both the interleukin 4 and interleukin 13 pathways. The drug, which was approved for clinical use in 2017, is safe, very effective, and has helped many eczema patients improve, Kim said. Patients typically receive injections of the drug twice a month. However, about 60% of those treated with the drug in clinical trials did not respond as well as their doctors would have liked. In addition, some patients see improvement on most of the body but experience flare-ups on the face. There also are side effects in some patients, such as conjunctivitis.
Side effects also limit the use of steroids. “Using steroids day in and day out is not advisable because it can contribute to thinning of the skin, which can contribute to other side effects,” Kim pointed out. “Long-term use can lead to easy bruising and even stretch marks on the skin. We need more reliable treatments to bring relief, and we think boosting NK cells may be one way to do that.”
Before embarking on the current study, Kim had noticed that his patients tend to have very low levels of NK cells in their blood. “We were perplexed as to why that might be, but the numbers were low enough, consistently enough, that eventually we started using them almost like a diagnostic tool,” he explained. “If we had any doubt about whether a person had eczema, we’d take a blood sample and look at their NK cell levels.”
To further explore the NK connection, Kim and Madison Mack, PhD, a graduate student in immunology, took Kim’s clinical observation to the laboratory and a mouse model of the skin disease. After removing the animals’ ability to make NK cells, Mack noticed that markers of inflammation in the animals worsened. Later, when they used an investigational drug prototype to increase the number of NK cells in the animals, inflammation lessened, and the mice got better.
Kim said he believes that in addition to improving skin rash associated with eczema, boosting the numbers of NK cells could help restore immunity to viruses in eczema patients. People who have very low numbers of NK cells turn out to be more susceptible to the herpes virus, pox viruses, and human papillomavirus, among other viruses.
Kim is eager to see if the strategy of revving up part of the immune system might help eczema patients. Investigational drugs that increase NK cell populations are being tested as treatments for some types of cancer in clinical trials at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. Kim said those studies suggest the drugs selectively boost NK cells, so he is now working with researchers from Siteman to test them in a clinical trial targeting eczema.
“We have a patent pending for this strategy, and we’re planning to move toward trials,” he stated. “And we won’t limit our studies to eczema. This strategy could help patients who have asthma or food allergies, conditions that often appear along with eczema.”
