Natural Killer Cell Regulation of Skin Inflammation

项目总结 以慢性皮肤炎症为特征的特应性皮炎(AD)是最常见的慢性疾病 儿童时期患病，往往是终生疾病。多种免疫细胞类型与AD有关 发病机制，包括肥大细胞、嗜碱性粒细胞和辅助性T细胞2型(Th2)细胞。金实验室最近的研究 发现组2先天淋巴样细胞(ILC2s)是AD/AD样病发生的关键因素 通过产生2型细胞因子IL-4和IL-13。事实上，阻断IL-4和IL-13受体(IL-13) 4R)已成为美国食品和药物管理局批准的第一种治疗中重度AD的靶向疗法。尽管如此， 在第三阶段临床试验中，40%的AD患者在疾病方面达到了主要终点 进步。对免疫的不完全理解阻碍了AD新疗法的开发 调节疾病的细胞类型超出了2型免疫细胞。迫切需要纠正这一点 开发有效的AD治疗方法的知识差距。我们的长期目标是针对AD的免疫调节器 来开发新的治疗方法。我们建议的总体目标是确定免疫细胞的类型和效应器 调控类AD疾病的机制。我们的中心假设是循环中的自然杀伤(NK)细胞 皮肤中2型炎症的主要调节剂，可用于治疗AD。NK细胞一直是 通过产生细胞溶解蛋白和干扰素参与抗肿瘤和抗病毒免疫- γ-干扰素()。最近的研究表明，NK细胞可能对肺内的ILC2进行负向调节，但其作用 皮肤和AD中的NK细胞仍不清楚。在初步研究中，我们发现小鼠的NK细胞 体内抑制皮肤ILC2反应。在人类中，我们发现循环血中的NK细胞明显 缺乏中到重度阿尔茨海默病，并随着疾病的解决而增加。这项提议的理由是 一旦了解了NK细胞如何影响AD的发病机制，就可以利用这些机制来创造 有效和新颖的阿尔茨海默病疗法。

PROJECT SUMMARY Characterized by chronic skin inflammation, atopic dermatitis (AD) is the most common chronic illness of childhood and is often a lifelong disease. Numerous immune cell types have been implicated in AD pathogenesis, including mast cells, basophils, and T helper type 2 (Th2) cells. Recent studies by the Kim Lab identified group 2 innate lymphoid cells (ILC2s) as critical contributors to development of AD/AD-like disease through production of the type 2 cytokines IL-4 and IL-13. Indeed, blockade of the IL-4 and IL-13 receptor (IL- 4R) has emerged as the first FDA-approved targeted therapy for moderate-to-severe AD. Despite this major advance, <40% of AD patients in phase III clinical trials met the primary endpoint in terms of disease improvement. Development of new AD therapies is hindered by an incomplete understanding of the immune cell types that regulate the disease beyond type 2 immune cells. There is an urgent need to correct this knowledge gap to develop effective therapies for AD. Our long-term goal is to target immune regulators of AD to develop new therapies. The overall objective of our proposal is to identify the immune cell types and effector mechanisms that regulate AD-like disease. Our central hypothesis is that circulating natural killer (NK) cells are major regulators of type 2 inflammation in the skin that can be harnessed to treat AD. NK cells have been implicated in antitumor and antiviral immunity through their production of cytolytic proteins as well as interferon- gamma (IFN-). Recent studies suggest that NK cells may negatively regulate ILC2s in the lung, but the role of NK cells in the skin and AD remains unclear. In preliminary studies, we revealed that mouse NK cells critically suppress skin ILC2 responses in vivo. In humans, we identified that circulating blood NK cells are markedly deficient in moderate-to-severe AD and increase with disease resolution. The rationale for this proposal is that once it is understood how NK cells influence AD pathogenesis, these mechanisms can be harnessed to create effective and novel AD therapies.