Restoring Immune Balance in Hiddradenitis Suppurativa

恢复化脓性汗腺炎的免疫平衡

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要 Hidradenenitis purativa（HS）是一种慢性衰弱的炎症性皮肤病。尽管患病率很高，并且发病率，HS研究了，目前尚无针对这种情况的有效治疗方法。阐明由于缺乏综合研究检查了这种疾病的免疫学。这一事实使这一事实更加复杂目前，没有动物模型可以准确地概括HS皮肤中看到的发现。我们已经组装了一个 UCSF研究人员的纪律团队，以更好地了解HS在细胞和分子水平。这集中在最近建立的“ UCSF Hidradenitis Purpurativa卓越中心” （HSCE），一家专门用于为HS患者提供一流护理并在此进行翻译研究的诊所疾病。有了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步，包括对调节T细胞（TREG）室中缺陷的新观察结果。特雷格通常居住在头发周围卵泡并调节嗜中性炎性炎症和皮肤纤维化，这是HS皮肤的两个病理标志。我们的初步结果表明，在HS患者的皮肤中，Treg在定量和质量上有缺陷。我们假设TH17免疫反应功能失调的Treg介导的控制在 HS的发病机理以及纠正这种不平衡将有效改善炎症并恢复组织免疫稳态。该提案中概述的实验将在功能上剖析细胞和分子控制HS皮肤中Treg/Th17平衡的机制。我们开发了一种创新的离体免疫细胞测定使用HS皮肤。此外，我们已经开始建立一个人源化的HS小鼠模型，该模型概括了这些患者的患病皮肤中观察到炎性浸润。在这些新建立的模型系统中，我们将利用一种优先结合高亲和力IL-2受体的新型分子来确定是否选择性 Treg增强可减轻HS皮肤的炎症。此外，我们最近发现了两个细胞表面受体优先表达在人皮肤，CD27和OX40中的受体，在抑制Th17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Treg中的Th17分化通过信号通过CD27和/或OX40恢复HS中的免疫平衡。该提案中概述的实验在概念和技术上是一种创新，全面和多学科的方法，以阐明如何 Treg/Th17分化轴的功能操纵会影响HS皮肤的炎症。 Th17途径人类皮肤主要是在牛皮癣中研究的，现在为牛皮癣开发了几种治疗方法被考虑用于HS。因此，本文提出的研究结果既及时又相关，以此更好地了解HS的发病机理，并确定牛皮癣中靶向的免疫途径是否可能转化为这种疾病。