Translation & trials: advancing medical countermeasure development

芥子气和芥末相关化合物是烷基化物质，会导致严重的上皮和深层组织 急性发炎、硬结、浮肿和接触时起水泡的损伤。潜在的 氮芥末(NM)和硫芥子气(SM)暴露后的组织损伤机制复杂。 在皮肤最初直接受伤后，免疫细胞大量涌入，为破裂的皮肤提供防御 但会产生不利的炎症，最终导致免疫风暴，引发一连串的 组织损伤。SM的历史使用表明，其后果超出了皮肤表面。我们的 研究小组已表明，通过系统抑制激活的巨噬细胞，大剂量维生素D可以改善 既有局部皮肤损伤，也有深层组织损伤。鉴于接触芥末造成的全部伤害可归因于 毒剂和免疫系统的活动，认为单一的对策可能是天真的 可以充分、全面地缓解芥末的影响。我们将利用我们在NM方面的经验 和SM，以及从人体内暴露的NM和大型动物的SM获得银行组织，以用作 为破解皮肤隔间和免疫隔间的信号奠定基础。芥末露皮肤 外植体将进行免疫表型鉴定，收获的培养上清液将用于刺激 幼稚的外周血液免疫细胞。我们的人芥末皮肤外植体和培养上清(缪斯)实验 SETUP与暴露在SM中的活体人类皮肤的特征相似，并将使研究能够描绘 由皮肤和免疫隔间产生的炎症因子。缪斯女神的炎症特征将是 在接受癌前疾病现场治疗的患者中使用我们的活体人体临床试验的组织进行验证 皮肤护理。鉴于皮肤表型反应的惊人相似之处，我们可以收集信息 从活体人体暴露模型来测试我们的两种对策。临床结果与新的 标志性分子靶点将促进5-FU患者的概念验证(POC)临床试验(延迟开始 3-5年)。我们的对策是用维生素阻断皮肤免疫细胞的激活 D3或用PLGA免疫修饰微粒阻止它们进入皮肤。这种综合方法的目的是 在限制细胞因子的激增和抑制皮肤中释放的下游组织基质因子。目标 这个项目的目的是更好地了解皮肤和免疫系统的反应，使用人类 组织和试验以开发医学对策。

Mustard gas and mustard-related compounds are alkylating agents that cause severe epithelial and deep tissue injury characterized by acute inflammation, induration, edema, and blistering upon contact. The underlying mechanism of tissue damage following exposure to nitrogen mustard (NM) and sulfur mustard (SM) is complex. After the initial direct injury to the skin there is an influx of immune cells that provide a defense to a breached epithelium but can produce unfavorable inflammation culminating in an immune storm that sets off a cascade of tissue injury. Historic use of SM demonstrates that the consequences extend beyond surfaces of the skin. Our group has shown by suppressing activated macrophages systemically with high dose vitamin D can ameliorate both local skin and deeper tissue injury. Given that the totality of injury from mustard exposure is attributable to the toxic agent and the activities of the immune system, it may be naive to consider that a single countermeasure can adequately and comprehensively mitigate the effects of mustard. We will leverage our experience with NM and SM, and access to banked tissue from in vivo NM exposure in humans and SM in large animals, to serve as a foundation to unravel the signals in the skin compartment vs. the immune compartment. Mustard exposed skin explants will be immunophenotyped and the harvested culture supernatants will be used to stimulate activation of naïve peripheral blood immune cells. Our human Mustard Skin Explant and Supernatant (MuSES) experimental setup approximates features of human skin in vivo, exposed to SM and will enable studies that delineate inflammatory factor production by the skin and immune compartments. Inflammation profiles from MuSES will be validated using tissue from our in vivo human clinical trials in patients undergoing field treatment for precancerous skin treatments. Given the remarkable resemblance of the skin phenotype reaction, we can gather information from in vivo human exposure models to test our two countermeasures . Clinical outcomes coupled with novel signature molecular targets will facilitate proof-of-concept (POC) clinical trials in 5-FU patients (delayed start to years 3-5). Our countermeasure strategies are to block the activation of skin infiltrating immune cells with vitamin D3 or block their entry into the skin with PLGA-immune modifying microparticles. This combined approach is aimed at limiting the surge of cytokines and inhibiting downstream tissue matrix factors released in the skin. The goals of this project are to better understand reactions of the skin and immune system using a combination of human tissue and trials to develop medical countermeasures.