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：
9803502
负责人：
Eynav Yafit Klechevsky
金额：
$ 34.54万
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/9803502
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 Cell Activation 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 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：牛皮癣是一种令人衰弱的自身免疫性疾病，影响了全球1.25亿人。而有些患者可以通过现有的非特异性疗法成功治疗，迫切需要开发新的目标皮肤中的T细胞秘密炎症细胞因子促进慢性病变。我们的实验室和其他人的研究表明，这些炎症性T细胞反应由树突状细胞（DCS）编程。皮肤直流系统复杂，已完成不同的子集，每个都有独特的接收器，用于诱导免疫复杂或免疫耐受性。广泛的理解在牛皮癣中促进炎症T细胞反应的DC的类型和独特的信号是一个缺口仍然是为患者设计急需的救济至关重要的。该应用的重点是我们最近发现的皮肤中新的人类DC子集，该子集由CD5描绘表达。 CD5+ DC影响健康人皮肤的表皮和真皮，并且在它们激活效果和炎症性TH细胞反应的能力（包括CTL，TH1，TH17和TH22）。此外，这些DC在银屑病发炎的皮肤中明显更丰富，这表明它们至关重要发病机理的参与者。与这个概念一致，提供了新的初步数据以证明CD5 触发直流成熟和炎症T细胞激活的炎症途径的功能。 CD5缺陷激活后，DC产生的炎症细胞因子较少，而激活T细胞的效率低于WT DC。此外，CD5 - / - 小鼠在牛皮癣的小鼠模型中表现出减少的病理。这些结果进一步任务调查表达CD5的DC对皮肤免疫的影响及其对牛皮癣的潜在探索治疗。我们的中心假设是： CD5代表了DC上的一种新型免疫刺激分子，并且对比例或比例的改变 CD5+ DC的功能对自身免疫有显着贡献。为了测试这一点，在AIM 1中，我们提出了实验以确定DCS收藏夹中CD5的机制激活和抗原摄取以启动T细胞免疫； AIM 2将确定CD5是否驱动T细胞介导的通过使用我们开发的新小鼠，该小鼠在牛皮癣皮肤中发炎，该小鼠专门在DC上缺乏CD5；和在AIM 3中，我们将定义银屑病患者皮肤中CD5+ DC的解剖分布，身体相互作用免疫细胞和自动反应性T细胞的激活。预计这些研究将导致CD5-对免疫调节的免疫调节的新基本见解表达DC，并将直接影响针对和停用DC的策略，从而实现安全和牛皮癣和其他炎症性疾病的有效应用。