Pathogenesis and Treatment of Atopic Dermatitis

特应性皮炎的发病机制和治疗

• 批准号: 8745528
• 负责人: Joshua Milner
• 金额: $ 59.62万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745528
• 关键词: Acute; Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Anaphylaxis; Antibody Specificity; Asthma; Atopic Dermatitis; Biological Assay; Caring; Cell Degranulation; Cell physiology; Chronic Granulomatous Disease; Clinical Immunology; Collaborations; Defect; Dermatitis; Disease; Drops; Enrollment; Etiology; Exanthema; Experimental Models; Food Hypersensitivity; Genetic; Goals; Hereditary Disease; Human; Hydrocortisone; Hypersensitivity; IgE; Immune; Immunologic Deficiency Syndromes; In Vitro; Incidence; Individual; Job' s Syndrome; Journals; Measures; Mediator of activation protein; Memory; Mus; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outpatients; Pathogenesis; Pathway interactions; Patients; Procedures; Protocols documentation; Quality of life; Recording of previous events; Refractory; Regulatory T-Lymphocyte; Reporting; Role; STAT3 gene; Safety; Series; Signal Transduction; Staging; Syndrome; T-Cell Immunologic Specificity; T-Lymphocyte; Time; United States National Institutes of Health; atopy; cohort; crosslink; eosinophil; follow-up; mast cell; mouse model; novel; screening; standard of care; success

The two main protocols for this project have been approved and are in active recruitment and accrual stages now. We continue to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency. We have a substantial cohort of patients with genetic disorders, which include atopy as a part of the syndrome (now numbering over 200 patients total). Three main findings have occurred in this project within the past year, describted in detail below. Finding 1: In order to assess the effects of STAT3 mutations on allergic disease, we performed detailed allergic histories on the majority of the NIH AD-HIES (autosomal dominant hyper-IgE syndrome)cohort and compared them to patients with marked IgE elevations but no STAT3 mutation. Patients with HIES had a substantially lower incidence of food allergy, asthma and anaphylaxis compared to those with similarly elevated IgE levels. Allergen-specific IgE was measured using ImmunoCap RAST and prominent allergen-specific IgE was measured in most patients, arguing against a defect in antibody specificity. Foxp3+ regulatory T cells (Tregs) have been shown to directly inhibit mast cell function, and many models of experimental atopy can be suppressed with regulatory T cells. We enumerated Foxp3+ T cells in HIES patients and found that within the diminished central memory compartment, there is a marked enrichment of Tregs compared to control. We have also shown that the defect appears primarily to be in mast cells, as STAT3 knockdown of human mast cells leads to marked reduction in the capacity for degranulation, and to a proximal signaling defect. Using a mouse model of AD-HIES in collaboration with Drs. Juan Rivera and John O'Shea's labs (NIAMS) we found that systemic IgE crosslinking or addition of mast cell secretagogue leads to impaired anaphylaxis in AD-HIES mice compared to controls. We have therefore identified STAT3 as a critical mediator of acute mast cell degranulation via the study of allergic disease in this rare immune deficiency. This report is in press at the Journal of Allergy and Clinical Immunology. Finding 2: Wet-wrap therapy is a mainstay of care for our patients with severe atopic dermatitis regardless of underlying etiology. We have now performed this therapy on over 50 patients refractory to the outpatient standard of care. We have found that while there is a transient drop in morning cortisol levels, this recovers, and there are few short or long term adverse affects of this therapy. We also found that there is an acute drop in circulating eosinophils, but this too recovers over time. Despite that, the long-term improvement in objective rash burden as well as subjective quality of life measures is quite significant and never before observed for such a prolonged follow up period in such a diverse patient group. In addition, we have performed this procedure on a variety of different immune deficiencies, including Chronic Granulomatous Disease, Dock8 deficiency, and STAT3 deficiency. Our success in those patients has both demonstrated the safety and the utility of the wraps in those conditions.

该项目的两个主要协议已获得批准，并且正在积极招聘和应计阶段。我们将继续仅招募一群患有严重特应性皮炎（AD）的患者，而在免疫缺陷的背景下患有AD的患者。我们有大量的遗传疾病患者队列，其中包括特应性作为综合征的一部分（现在总共有200多名患者）。在过去的一年中，该项目发生了三个主要发现，下面详细描述了。 发现1：为了评估STAT3突变对过敏性疾病的影响，我们对大多数NIH AD-HIE（常染色体显性高IGE综合征）的详细过敏史进行了比较，并将其与具有明显的IGE升高患者进行了比较。与IgE水平升高的患者相比，HIS患者的食物过敏，哮喘和过敏反应的发生率大大降低。 使用免疫胶带测量过敏原特异性IgE，并在大多数患者中测量明显的过敏原特异性IgE，反对抗体特异性缺陷。 FOXP3+调节性T细胞（Tregs）已显示可直接抑制肥大细胞功能，许多实验模型可以被调节性T细胞抑制。我们列举了HIES患者的Foxp3+ T细胞，发现在中央记忆室减少的情况下，与对照相比，Tregs明显富集。 我们还表明，由于人类肥大细胞的STAT3敲低导致脱粒能力显着降低，并且导致近端信号传导缺陷，因此缺陷似乎主要是在肥大细胞中。使用与DRS合作的AD-HIE的鼠标模型。胡安·里维拉（Juan Rivera）和约翰·奥希亚（John O'Shea）的实验室（NIAMS）我们发现，与对照组相比，Ad-Hies小鼠的全身IGE交联或添加会导致Ad-Hies小鼠的过敏反应受损。因此，我们通过研究这种罕见的免疫缺乏，将STAT3确定为急性肥大细胞脱粒的关键介质。该报告在《过敏和临床免疫学杂志》上发表。 查找2： 湿包疗法是针对严重特应特应性皮炎的患者的主要护理，无论其潜在病因如何。现在，我们对50多名患者对门诊护理标准进行了这种疗法。我们发现，尽管早晨皮质醇水平有短暂的下降，但这恢复了，这种疗法的短期或长期不利影响几乎没有。我们还发现，循环嗜酸性粒细胞急剧下降，但随着时间的流逝，这也恢复了。尽管如此，在如此多样化的患者组中，客观皮疹负担的长期改善和主观生活质量措施的长期改善非常重要，并且从未观察到如此长时间的随访期。此外，我们已经对各种不同的免疫缺陷进行了此程序，包括慢性肉芽肿性疾病，Dock8缺乏症和STAT3缺乏症。我们在这些患者中的成功都证明了这些条件下包裹的安全性和实用性。