Natural Killer Cell Regulation of Skin Inflammation

项目摘要 特应性皮炎（AD）是人类最常见的慢性疾病，其特征为慢性皮肤炎症。 儿童期，往往是一种终身疾病。许多免疫细胞类型与AD有关 发病机制，包括肥大细胞，嗜碱性粒细胞和T辅助2型（Th 2）细胞。Kim实验室的最新研究 确定第2组先天淋巴样细胞（ILC 2）是AD/AD样疾病发生的关键因素 通过产生2型细胞因子IL-4和IL-13。事实上，IL-4和IL-13受体（IL-13）的阻断可以抑制IL-13的表达。 4 R β）已成为FDA批准的第一种用于中重度AD的靶向治疗。尽管这一重大 在III期临床试验中，<40%的AD患者达到了疾病的主要终点。 改进.新的AD疗法的开发受到对免疫系统的不完全理解的阻碍。 调节疾病的细胞类型超过2型免疫细胞。这一点迫切需要纠正 知识差距，以开发有效的治疗AD。我们的长期目标是针对AD的免疫调节剂 来开发新的疗法我们的建议的总体目标是确定免疫细胞类型和效应子。 调节AD样疾病的机制。我们的中心假设是，循环自然杀伤（NK）细胞是 皮肤中2型炎症的主要调节剂，可用于治疗AD。NK细胞已 通过产生细胞溶解蛋白以及干扰素- γ（IFN-γ）。最近的研究表明，NK细胞可能负调节肺中的ILC 2，但NK细胞的作用可能与IL-2的表达有关。 皮肤中的NK细胞和AD仍不清楚。在初步的研究中，我们发现小鼠NK细胞 抑制体内皮肤ILC 2反应。在人类中，我们发现循环血液NK细胞明显增加， 在中度至重度AD中缺乏，并随着疾病消退而增加。提出这一建议的理由是， 一旦了解了NK细胞如何影响AD发病机制，这些机制就可以用来创造 有效和新颖的AD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.