Restoring Immune Balance in Hiddradenitis Suppurativa

恢复化脓性汗腺炎的免疫平衡

• 批准号: 10410361
• 负责人: Michael David Rosenblum
• 金额: $ 69.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410361
• 关键词: Affect; Affinity; Age; Animal Model; Applications Grants; Attenuated; Basic Science; Binding; Biological Assay; Biological Models; Biopsy Specimen; Caring; Cell Lineage; Cell Surface Receptors; Cells; Cellular Assay; Chronic; Clinic; Cutaneous; Data; Defect; Development; Disease; Epigenetic Process; Equilibrium; Evaluation; Fibrosis; Flow Cytometry; Foundations; Functional disorder; Gender; Genetic Transcription; Hair follicle structure; Health; Hidradenitis Suppurativa; High Prevalence; Homeostasis; Human; Immune; Immune response; Immune system; Immunology; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin 2 Receptor; Interleukin-17; Interleukin-2; Laboratories; Lesion; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; OX40; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Proteins; Psoriasis; Regulatory T-Lymphocyte; Research Personnel; Role; Signal Transduction; Sinus; Site; Skin; Testing; Therapeutic; Time; Tissues; Translational Research; Tumor Necrosis Factor Receptor; Validation; base; chronic inflammatory disease; chronic inflammatory skin; effective therapy; experience; experimental study; humanized mouse; immunopathology; in vivo; innovation; interdisciplinary approach; member; mouse model; multidisciplinary; neutrophil; novel; novel strategies; novel therapeutic intervention; response; single-cell RNA sequencing; skin disorder; skin fibrosis; skin lesion; skin organogenesis; tool; translational study; treatment strategy

Project Summary/Abstract Hidradenitis Suppurativa (HS) is a chronic debilitating inflammatory skin disease. Despite its high prevalence and morbidity, HS is understudied, and there is currently no uniformly effective treatment for this condition. Elucidation of disease pathogenesis, target identification and evaluation of novel treatments has been limited by the lack of comprehensive studies examining the immunology of this disease. This is compounded further by the fact that there are currently no animal models that accurately recapitulate the findings seen in HS skin. We have assembled a multi- disciplinary team of investigators at UCSF to better understand the immunopathogenesis of HS at both the cellular and molecular levels. This is centered around the recently established 'UCSF Hidradenitis Suppurativa Center of Excellence' (HSCE), a clinic dedicated entirely to providing first-rate care for HS patients and performing translational studies in this disease. With the HSCE, my laboratory has made significant advances in our understanding of the immunology of HS, including new observations of defects in the regulatory T cell (Treg) compartment. Tregs normally reside around hair follicles and regulate both neutrophilic inflammation and dermal fibrosis, two pathologic hallmarks of HS skin. Our preliminary results suggest that Tregs are both quantitatively and qualitatively defective in skin of HS patients. We hypothesize that dysfunctional Treg-mediated control of Th17 immune responses plays a central role in the pathogenesis of HS and that correcting this imbalance will effectively ameliorate inflammation and restore tissue immune homeostasis. Experiments outlined in this proposal will functionally dissect the cellular and molecular mechanisms controlling the Treg/Th17 balance in HS skin. We have developed an innovative ex vivo immune cell assay using HS skin. In addition, we have begun to establish a humanized mouse model of HS that recapitulates the inflammatory infiltrate observed in diseased skin of these patients. In these newly established model systems, we will utilize a novel molecule that preferentially binds to the high affinity IL-2 receptor to functionally determine if selective Treg augmentation attenuates inflammation in HS skin. In addition, we have recently discovered two cell surface receptors preferentially expressed on Tregs in human skin, CD27 and OX40, that play a major role in inhibiting Th17 differentiation in these cells. In separate experiments, we will determine whether inhibiting Th17 differentiation in Tregs via signaling through CD27 and/or OX40 restores immune balance in HS. The experiments outlined in this proposal represent a conceptually and technically innovative, comprehensive, and multidisciplinary approach to elucidate how functional manipulation of the Treg/Th17 differentiation axis influences inflammation in HS skin. The Th17 pathway in human skin has primarily been studied in psoriasis and several therapeutic approaches developed for psoriasis are now being considered for HS. Thus, the results of the studies proposed herein are both timely and relevant, in our attempts to better understand the pathogenesis of HS and determine whether immune pathways targeted in psoriasis may or may not translate to this disease.

项目总结/摘要 化脓性汗腺炎（HS）是一种慢性使人衰弱的炎症性皮肤病。尽管其发病率很高， 由于发病率高，HS的研究还不够，目前还没有针对这种情况的统一有效的治疗方法。阐明 疾病的发病机制，靶点鉴定和新治疗方法的评价受到缺乏 全面研究了这种疾病的免疫学。这一点由于以下事实而更加复杂： 目前没有动物模型能准确地概括HS皮肤中观察到的发现。我们已经建立了一个多- 加州大学旧金山分校的一个学科研究小组，以更好地了解HS在细胞和 分子水平。这是围绕最近成立的'UCSF Hidradenitis Suppurativa卓越中心' （HSCE），一家完全致力于为HS患者提供一流护理的诊所，并在此领域进行转化研究。 疾病通过HSCE，我的实验室在我们对HS免疫学的理解方面取得了重大进展， 包括对调节性T细胞（Treg）区室缺陷的新观察。毛发通常位于头发周围 毛囊和调节嗜酸性炎症和真皮纤维化，HS皮肤的两个病理标志。我们 初步结果表明，HS患者皮肤中的TdR在数量和质量上都有缺陷。我们 假设功能失调Treg介导的Th 17免疫应答控制在Th 17免疫应答中起中心作用， HS的发病机制，纠正这种不平衡将有效地改善炎症和恢复组织 免疫稳态本提案中概述的实验将从功能上剖析细胞和分子 控制HS皮肤中Treg/Th 17平衡的机制。我们开发了一种创新的体外免疫细胞检测方法 使用HS皮肤。此外，我们已经开始建立HS的人源化小鼠模型，其重现了 在这些患者患病皮肤中观察到炎性浸润。在这些新建立的模型系统中，我们将 利用优先结合高亲和力IL-2受体的新分子，以在功能上确定选择性 Treg增强减弱HS皮肤中的炎症。此外，我们最近发现了两种细胞表面 在人皮肤中优先表达在Th 17上的受体，CD 27和OX 40，其在抑制Th 17中起主要作用 这些细胞的分化。在单独的实验中，我们将确定是否抑制Th 17分化在T细胞中， 通过CD 27和/或OX 40的信号传导恢复HS中的免疫平衡。本提案中概述的实验 代表了一种概念和技术创新，全面和多学科的方法，以阐明如何 Treg/Th 17分化轴的功能性操作影响HS皮肤中的炎症。Th 17通路 人类皮肤主要用于银屑病研究，目前已开发出几种治疗银屑病的方法 正在考虑HS。因此，本文提出的研究结果是及时和相关的，在我们的尝试， 更好地了解HS的发病机制，并确定银屑病中靶向的免疫途径是否可能 转化为这种疾病。