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：
10642826
负责人：
Michael David Rosenblum
金额：
$ 70.97万
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/10642826
关键词：
Abnormal Cell Acceleration Affect Affinity Age Animal Model Applications Grants Attenuated Basic Science Binding Biological Assay Biological Models Biopsy Specimen Caring Cell Compartmentation Cell Lineage Cell Separation Cell Surface Receptors Cell physiology Cells Cellular Assay Chronic Clinic Cutaneous Data Dedications 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 IL17 gene Immune Immune response Immune system Immunology Infiltration Inflammation Inflammatory Inflammatory Infiltrate Interleukin 2 Receptor 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 Tissues Translational Research Tumor Necrosis Factor Receptor Validation 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.

项目概要/摘要化脓性汗腺炎 (HS) 是一种慢性衰弱性炎症性皮肤病。尽管其患病率很高并且 HS 的发病率尚未得到充分研究，目前还没有针对这种情况的统一有效的治疗方法。阐明由于缺乏相关研究，疾病发病机制、靶点识别和新疗法的评估受到了限制。检查这种疾病的免疫学的综合研究。由于存在以下事实，情况变得更加复杂：目前还没有动物模型能够准确重现 HS 皮肤中的发现。我们已经组装了一个多 UCSF 的学科研究小组旨在更好地了解 HS 的细胞和免疫发病机制分子水平。该项目以最近成立的“UCSF 化脓性汗腺炎卓越中心”为中心 (HSCE)，一家完全致力于为 HS 患者提供一流护理并在此领域开展转化研究的诊所疾病。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。 Tregs 通常存在于头发周围毛囊并调节中性粒细胞炎症和真皮纤维化，这是 HS 皮肤的两个病理特征。我们的初步结果表明，热射病患者皮肤中的Tregs在数量和质量上均存在缺陷。我们假设功能失调的 Treg 介导的 Th17 免疫反应控制在 HS 的发病机制，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从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法使用HS皮肤。此外，我们已经开始建立 HS 人源化小鼠模型，该模型概括了在这些患者的患病皮肤中观察到炎症浸润。在这些新建立的模型系统中，我们将利用优先与高亲和力 IL-2 受体结合的新型分子来功能性地确定是否具有选择性 Treg 增强可减轻 HS 皮肤的炎症。此外，我们最近还发现了两种细胞表面优先表达在人类皮肤 Tregs 上的受体 CD27 和 OX40，在抑制 Th17 中发挥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 Tregs 中的 Th17 分化通过 CD27 和/或 OX40 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上创新的、全面的、多学科的方法来阐明如何 Treg/Th17 分化轴的功能调控影响 HS 皮肤炎症。 Th17 途径人类皮肤主要针对牛皮癣进行了研究，目前已开发出几种针对牛皮癣的治疗方法正在考虑HS。因此，本文提出的研究结果既及时又相关，我们试图更好地了解 HS 的发病机制并确定银屑病的免疫途径是否有效翻译成这个病。