Harnessing Human Dendritic Cell Subsets in Skin for the Design of Novel Immunotherapies

利用皮肤中的人类树突状细胞亚群来设计新型免疫疗法

基本信息

批准号：
10440456
负责人：
Eynav Yafit Klechevsky
金额：
$ 34.3万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-04 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440456
关键词：
Address Affect American Anatomy Antigen Presentation Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmunity Biological Assay CD34 gene CRISPR/Cas technology Cell Maturation Cell physiology Cells Chronic Coculture Techniques Complement Cross Presentation Cytometry Data Dendritic Cell Pathway Dendritic Cells Dendritic cell activation Dermis Development Disease Distal Epidermis Epithelial Flare Frequencies Goals Homeostasis Human Image Immune Immune Tolerance Immune response Immune system Immunity Immunomodulators Immunosuppression Immunotherapy Inflammation Inflammatory Inflammatory Response Interferon Type II Interleukin-17 Investigation Knockout Mice Laboratories Lesion Lipids Lymphoid MHC Class I Genes Malignant Neoplasms Mediating Modification Mouse Strains Mus Mutate Opportunistic Infections Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peptides Persons Production Psoriasis Publishing Recurrence Role Signal Transduction Skin System T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TNF gene Technology Testing Therapeutic Intervention Tissues Work antigen-specific T cells autoreactive T cell base cell type cytokine design effector T cell experimental study immune activation immunoregulation in vivo insight interleukin-22 lymph nodes migration mortality mouse model new therapeutic target novel prevent progenitor receptor response scavenger receptor side effect single-cell RNA sequencing synergism targeted treatment treatment response uptake

项目摘要

ABSTRACT: Psoriasis is a debilitating auto-immune disease that affects 125 million people worldwide. While some patients can be treated successfully with existing non-specific therapies, there is a dire need for developing new targeted treatments that are durable and have on side effects. T cells in the skin that secrete inflammatory cytokines promote chronic lesions. Studies by our lab and others have shown that these inflammatory T cell responses are programmed by dendritic cells (DCs). The skin DC system is intricate and is comprised of distinct subsets, each with unique receptors for inducing either immune responses or immune tolerance. Extensive understanding of the type of DC and the unique signals that promote inflammatory T cell responses in psoriasis is a gap that remains and essential for designing much needed relief for patients. This application focuses on our recent discovery of a new human DC subset in skin that is delineated by CD5 expression. The CD5+ DC inhabit both the epidermis and the dermis of healthy human skin and are superior in their capacity to activate effectors and inflammatory TH cell responses (including CTLs, TH1, TH17 and TH22). Moreover, these DCs are significantly more plentiful in psoriatic inflamed skin, which suggests they are critical players in pathogenesis. Consistent with this notion, new preliminary data are provided to demonstrate that CD5 functions to trigger an inflammatory pathway of DC maturation and inflammatory T cell activation. CD5-deficient DCs produce less inflammatory cytokines upon activation, and activates T cells less efficiently than WT DCs. Moreover, CD5-/- mice display reduced pathology in a mouse model of psoriasis. These results mandate further investigation of the impact of CD5-expressing DCs on skin immunity and their potential exploration for psoriasis therapy. Our central hypothesis is that: CD5 represents a novel immune-stimulatory molecule on DCs, and that alterations to the proportions or functions of CD5+ DCs contribute significantly to autoimmunity. To test this, in Aim 1 we propose experiments to determine the mechanisms by which CD5 on DCs facilitates activation and antigen uptake to initiate T cell immunity; Aim 2 will determine whether CD5 drives T cell–mediated inflammation in psoriatic skin by using a new mouse that we developed that lack CD5 specifically on DCs; and in aim 3 we will define the anatomic distributions of CD5+ DCs in skin of psoriatic patients, physical interactions with immune cells and activation of autoreactive T cells. It is anticipated that these studies will lead to new fundamental insights into immune regulation by CD5- expressing DCs and will have direct impact on strategies to target and deactivate DCs, leading to safe and effective applications for psoriasis and other inflammatory diseases in and beyond the skin.

抽象的：银屑病是一种使人衰弱的自身免疫性疾病，影响着全世界 1.25 亿人，而一些患者也受到影响。可以用现有的非特异性疗法成功治疗，迫切需要开发新的靶向疗法持久且对皮肤中分泌炎症细胞因子的 T 细胞有副作用的治疗。我们实验室和其他人的研究表明，这些炎症 T 细胞反应会促进慢性病变。由树突状细胞 (DC) 编程皮肤 DC 系统非常复杂，由不同的子集组成，每种都有独特的受体来诱导免疫反应或免疫耐受。银屑病中 DC 类型和促进炎症 T 细胞反应的独特信号之间的差距对于为患者设计急需的缓解措施仍然至关重要。该应用重点关注我们最近在皮肤中发现的新的人类 DC 子集，该子集由 CD5 描述 CD5+ DC 存在于健康人体皮肤的表皮和真皮中，并且在以下方面表现出色。它们激活效应器和炎症 TH 细胞反应（包括 CTL、TH1、TH17 和 TH22）的能力。此外，这些树突状细胞在银屑病发炎的皮肤中明显更加丰富，这表明它们至关重要与这一观点一致，提供了新的初步数据来证明 CD5。其功能是触发 DC 成熟和 CD5 缺陷型炎症 T 细胞激活的炎症途径。 DC 激活后产生较少的炎症细胞因子，并且激活 T 细胞的效率低于 WT DC。此外，CD5-/-小鼠在银屑病小鼠模型中表现出病理学减轻，这些结果进一步说明了这一点。表达CD5的DC对皮肤免疫的影响及其治疗银屑病的潜在探索我们的中心假设是： CD5 代表 DC 上的一种新型免疫刺激分子，其比例或 CD5+ DC 的功能对自身免疫有显着贡献。为了测试这一点，在目标 1 中，我们提出了实验来确定 DC 上的 CD5 促进的机制激活和抗原摄取以启动 T 细胞免疫；目标 2 将确定 CD5 是否驱动 T 细胞介导使用我们开发的新小鼠来治疗银屑病皮肤炎症，该小鼠在 DC 上特异性缺乏 CD5；在目标 3 中，我们将定义银屑病患者皮肤中 CD5+ DC 的解剖分布、物理相互作用与免疫细胞和自身反应性 T 细胞的激活。预计这些研究将为 CD5- 免疫调节带来新的基本见解表达 DC 并将对针对和停用 DC 的策略产生直接影响，从而实现安全和有效治疗牛皮癣和其他皮肤内外炎症性疾病。