A murine model showed success in treating atopic dermatitis by activating natural killer cells instead of suppressing the immune response. The Dermatologist spoke with researcher Brian S. Kim, MD, about the future of this immunotherapeutic strategy.
Natural killer (NK) cells have long been thought to be associated with the severity of atopic dermatitis (AD). In the 1980s, several studies found a negative correlation between NK cell percentage and activity and AD disease activity, prompting more research on the role of NK cells in the immune response.1-4
Chiarelli et al1 found the function of NK cells was reduced in children with varying severities of AD, where increased clinical severity was associated with reduced NK cell activity. Lever et al3 noticed a similar trend among seven young adults with AD over a 12-month period, stating “the more active the disease, the greater was the reduction in NK cell function.” Jensen2 studied the phenomenon on a single cell assay, noticing the percentage of active NK cells was significantly reduced; Hall et al4 also used assays, further suggesting that the reduced number of NK cells account for the depressed level of their activity in patients with severe AD. French researchers connected both AD and psoriasis with quantitative and qualitative changes in peripheral NK cells, implicating them in the inflammatory skin diseases.5,6 It is understood that the immune system must be involved in the cause of eczema. However, no direct link or causation has been discovered despite solid evidence in the literature, and recent research on therapeutic strategies using NK cell response has been focused in oncology and autoimmunity.6
Additionally, patients with eczema are susceptible to a number of comorbidities, including other allergic responses (asthma, allergic rhinitis) and infections.7 In particular, persons with eczema are commonly affected by staphylococcal and herpetic infections. It can be postulated then that this is because of the abnormal immune response in patients with AD. For example, Kawakami et al8 demonstrated deficient NK cell activities in herpes simplex virus (HSV) 1-infected AD-like murine models. Similarly, Goodyear et al9 hypothesized that the reduced number of circulating NK cells and IL-2 receptors could contribute to the susceptibility of children with atopic eczema to cutaneous HSV infection. NK cells are crucial to controlling and protecting HSV infection,10 as shown in a study on IL-15 and NK cell functions in murine vaginal HSV-2.11
“We have been interested in understanding the role of the immune response [in AD] for almost 10 years now,” stated Brian S. Kim, MD, a dermatologist and associate professor of medicine at Washington University School of Medicine in St Louis, MO. He also serves as the codirector of the Center for the Study of Itch & Sensory Disorders at Washington University. “Around 2013-2014, we identified that previously unrecognized or unappreciated cells, group 2 innate lymphoid cells [ILC2s] and basophils from the circulation, respectively, can cause atopic dermatitis. Then, in 2017, it became common knowledge that the drug dupilumab [Dupixent] is highly effective by blocking key proteins produced by these cells, namely IL-4 and IL-13. However, it has remained elusive as to what actually prevents these pathogenic cells from become overly activated.”
Taking this previous research, Dr Kim and colleagues from Washington University School of Medicine explored the relationship between AD and NK cells further. The group noted a dysregulated NK cell-associated gene signature in patients with AD.12 The study also demonstrated that NK cells repress ILC2s,12 which have been noted to be elevated in patients with AD.13 Agreeing with previously published literature,1-6,8,9 the group identified a significant decrease in overall NK cell count in patients with AD and suggested the reduced NK cell-mediated immunomodulation may promote atopic disease.12
“This started to make a lot of sense because we had known for decades that patients with atopic dermatitis do not control viruses in the skin well, and NK cells are very important to protect against a variety of viruses. We then speculated that perhaps this cell, which normally surveils and attacks viruses, may actually help to limit inflammation that causes atopic dermatitis. This was the ‘eureka’ link we made,” said Dr Kim.
The group’s latest study, published in Science Translational Medicine, proposes using an IL-15 superagonist to boost a patient’s number of NK cells in the blood, thereby reducing the inflammatory response to improve AD severity and, hopefully, restore viral immunity in patients with AD.14
This research, funded in part by LEO Pharma and the National Institutes of Health, could lead to an alternative therapy for patients with AD that differs from more conventional therapies that seek to suppress the immune system to stop the itch-scratch cycle of eczema and reduce the risk of skin infection.15 “Not everyone responds to suppressing their native immune response, thus this may offer an alternative treatment strategy for those who have not responded to new and emerging therapies,” said Dr Kim. “Additionally, this may be particularly well-suited for individuals who have low NK cells in the blood and/or those who suffer from viral complications like eczema herpeticum or eczema vaccinatum.” Dr Kim tied the viral complications to overall patient health, noting that the lowered NK cell levels may be a good explanation as to why some patients with eczema do not effectively fight off these certain viral infections.
In a press release, Dr Kim noted that his team often looks at the NK cell level of patient blood samples in the diagnosis of AD.16 “NK cells in the blood may be useful as a diagnostic and prognostic marker for how severe their disease is and how responsive they may be to therapy,” said Dr Kim. He stated that it is important to note that low NK cell count is not a definitive diagnostic feature, but it can be associated with the disease across populations of patients with moderate to severe AD.
The future of this immunotherapeutic strategy centers on
researching why NK cells are dysfunctional in eczema. Dr Kim and colleagues look to answer questions such as Why are some people born with defective NK cells and is that why they are susceptible to eczema? and Does having eczema for a long time permanently alter NK cells?. The team has filed a patent for the IL-15 superagonist technology and is working with Nuogen Pharma, Inc, to take steps toward bringing this therapy to patients.
“Furthermore,” continued Dr Kim, “we suspect that patients with other atopic disorders like asthma may also have similar defects. Time will tell as to how broadly this phenomenon impacts allergic disease in general.”
References
1. Chiarelli F, Canfora G, Verrotti A, Amerio P, Morgese G. Natural killer cell function in atopic dermatitis. Acta Paediatr Scand. 1988;77(2):275-278.doi: 10.1111/j.1651-2227.1988.tb10642.x
2. Jensen JR. Reduction of active natural killer cells in patients with atopic dermatitis estimated at the single cell level. Acta Derm Venereol Suppl (Stockh). 1985;114:105-108.
3. Lever RS, Lesko MJ, MacKie RM, Parrott DM. Natural killer cell activity in atopic dermatitis: a sequential study. Clin Allergy. 1985;15(5):479-486. doi:10.1111/j.1365-2222.1985.tb02298.x
4. Hall TJ, Rycroft R, Brostoff J. Decreased natural killer cell activity in atopic eczema. Immunology. 1985;56(2):337-344.
5. Luci C, Gaudy-Marqueste C, Rouzaire P, et al. Peripheral natural killer cells exhibit qualitative and quantitative changes in patients with psoriasis and atopic dermatitis. Br J Dermatol. 2012;166(4):789-796. doi:10.1111/j.1365-2133.2012.10814.x
6. Von Bubnoff D, Andrés E, Hentges F, Bieber T, Michel T, Zimmer J. Natural killer cells in atopic and autoimmune diseases of the skin. J Allergy Clin Immunol. 2010;125(1):60-68. doi: 10.1016/j.jaci.2009.11.020
7. Conditions related to eczema. National Eczema Association website. Accessed February 27, 2020. https://nationaleczema.org/eczema/related-conditions/
8. Kawakami Y, Ando T, Lee JR, et al. Defective natural killer cell activity in a mouse model of eczema herpeticum. J Allergy Clin Immunol. 2017;139(3):997-1006.e10. doi:10.1016/j.jaci.2016.06.034
9. Goodyear HM, McLeish P, Randall S, et al. Immunological studies of herpes simplex virus infection in children with atopic eczema. Br J Dermatol. 1996;134(1):85-93.
10. Cifaldi L, Doria M, Cotugno N, et al. DNAM-1 activating receptor and its ligands: how do viruses affect the NK cell-mediated immune surveillance during the various phases of infection? Int J Mol Sci. 2019;20(15):3715. doi:10.3390/ijms20153715
11. Ashkar AA, Rosenthal KL. Interleukin-15 and natural killer and NKT cells play a critical role in innate protection against genital herpes simplex virus type 2 infection. J Virol. 2003;77(18):10168-10171. doi:10.1128/jvi.77.18.10168-10171.2003
12. Mack M, Brestoff J, Niu H, et al. Natural killer cell dysregulation underlies atopic dermatitis. J Investig Dermatol. 2018;138(5 suppl):S172. doi:10.1016/j.jis.2018.03.1029
13. Doherty TA, Broide DH. Group 2 innate lymphoid cells: new players in human allergic diseases. J Investig Allergol Clin Immunol. 2015;25(1):1-11.
14. Mack MR, Brestoff JR, Berrien-Elliott MM. Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis. Sci Translat Med. 2020;12(532). doi:10.1126/scitranslmed.aay1005
15. Immunosuppressants. National Eczema Association website. Accessed February 28, 2020. https://nationaleczema.org/eczema/treatment/immunosuppressants/
16. Revving up immune system may help treat eczema website. Press release. Washington University School of Medicine; February 26, 2020. Accessed February 28, 2020. https://www.eurekalert.org/pub_releases/2020-02/wuso-rui022620.php
