Pathogenesis and Treatment of Atopic Dermatitis

特应性皮炎的发病机制和治疗

• 批准号: 8157080
• 负责人: Joshua Milner
• 金额: $ 40.22万
• 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/8157080
• 关键词: Atopic Dermatitis; Dermatitis; Pathogenesis; T-Cell Immunologic Specificity

This is the second report for this project. The two main protocols for this project have been approved and are in recruitment and accrual stages now. We have begun to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency-- a patient group whose comorbid immunodeficiency may help point towards the pathophysiology underlying the atopic dermatitis. We have also begun accruing patients with genetic disorders which include atopy as a part of the syndrome. Concurrently, we have begun to develop screening assays for a number of pathways predicted to be disrupted in atopic dermatitis. These include TCR signaling, TCR repertoire and STAT3 axis disruptions. We have been able to generate novel data using some of these tools on a number of patients enrolled in the protocols which we believe may begin to shed light on the pathogenesis of the atopic disease, and yield basic insights into human T-cell biology. We are now in the recruitment phase to begin to treat patients with severe refractory atopic dermatitis with Anakinra, the IL-1 receptor antagonist. Additionally, we have been able to study the role of STAT3 in lymphocyte homeostasis. STAT3 disruption leads to elevated IgE and atopic dermatitis in the Hyper-IgE syndrome (HIES). A patient with STAT3 mosaicism was identified in collaboration with Dr. Steve Holland's group in the Laboratory of Clinical Infectious Diseases, and by sorting lymphocyte populations and sequencing for the mutant we have been able to establish the relative contribution of the mutant allele to T- and B-cell intrinsic defects seen in HIES. These defects may have specific roles in the pathogenesis of the atopic aspect of HIES, and therefore have broader implications for atopic disease in general. Furthermore, we have also been able to demonstrate that a potential consequence of this defect is a markedly increased risk for herpes zoster in these patients. We are actively pursuing further mechanistic explanations, and plan to begin an immunization project to determine the efficacy of zoster immunization in this young cohort of patients who nonetheless develop shingles at a high rate.

这是该项目的第二个报告。该项目的两个主要协议已获得批准，并且正在招聘和应计阶段。我们已经开始单独参加严重特应性皮炎（AD）的患者，并且在免疫缺乏症的背景下患有AD的患者 - 一个患者组合性免疫缺陷的患者可能有助于指出原子性皮肤炎的病理生理学。我们还开始累积遗传疾病的患者，其中包括特应性作为综合征的一部分。同时，我们已经开始开发筛查测定法，以预测在特应性皮炎中被破坏的许多途径。其中包括TCR信号，TCR曲目和STAT3轴破坏。我们已经能够使用其中一些工具来生成新的数据，这些工具对许多参与方案的患者进行了我们认为可能开始阐明特应性疾病的发病机理，并对人类T细胞生物学产生基本见解。现在，我们处于招募阶段，开始使用IL-1受体拮抗剂Anakinra治疗严重难治性特应性皮炎的患者。 此外，我们还能够研究STAT3在淋巴细胞稳态中的作用。 STAT3破坏导致Hyper-Ige综合征（HIE）中的IgE和特应性皮炎升高。与史蒂夫·霍兰德（Steve Holland）博士的临床传染病实验室合作确定了患有STAT3镶嵌的患者，通过对突变体进行淋巴细胞群体和测序进行分类，我们能够确定突变体等位基因对T-和B-CELL的相对贡献。这些缺陷可能在HIS特应特应性的发病机理中具有特定的作用，因此对整个特应性疾病具有更广泛的影响。此外，我们还能够证明，这种缺陷的潜在结果显然增加了这些患者的疱疹带状疱疹的风险。 我们正在积极追求进一步的机械解释，并计划开始一个免疫项目，以确定带状疱疹免疫在这一年轻的患者中的功效，这些患者仍然以高速度开发带状疱疹。