The role of plasmacytoid dendritic cells in corneal immunity

浆细胞样树突状细胞在角膜免疫中的作用

基本信息

批准号：
10640026
负责人：
Pedram Hamrah
金额：
$ 50.76万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640026
关键词：
Acute Adoptive Transfer Affect Allogenic Anti-Inflammatory Agents Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Area Autoimmune Bone Marrow Candidate Disease Gene Cell Communication Cells Chimera organism Clinical Coculture Techniques Communicable Diseases Confocal Microscopy Cornea Corneal Diseases Corneal Injury Corneal Opacity Data Dendritic Cells Development Disease Disease Progression Dry Eye Syndromes Endowment Esthesia Feasibility Studies Fibrin Tissue Adhesive Gene Silencing Generations Grant Herpesvirus 1 Herpetic Keratitis Homeostasis Immune Immune System Diseases Immune response Immunity Infection Inflammation Inflammation Process Inflammatory Interferon Type II Interleukin-10 Investigation Keratitis Keratoplasty Kinetics Label Leucocytic infiltrate Leukocytes Lymphocyte Maintenance Measures Mediating Modeling Molecular Natural Immunity Nerve Outcome Property Regulatory T-Lymphocyte Role Severities Severity of illness Simplexvirus Stains Sterility Surgical sutures Survival Rate T-Cell Proliferation T-Lymphocyte TLR7 gene TNF gene Tissues Topical application Transforming Growth Factor beta Transgenic Mice Treatment Efficacy Viral Virus Diseases adaptive immune response adaptive immunity advanced disease candidate identification clinically relevant cytokine density draining lymph node effector T cell experimental study immune modulating agents immunoregulation improved in vivo multiphoton microscopy novel novel strategies phenotypic biomarker protein expression receptor recruit side effect single cell sequencing single-cell RNA sequencing spatiotemporal transplant model uptake

项目摘要

SUMMARY The cornea is among the few tissues that enjoy immune privilege, however, corneal immune privilege is not absolute. In many corneal diseases, including infectious keratitis, dry eye disease, and corneal injuries, infiltrating leukocytes can advance disease progression. Our preliminary results suggest that plasmacytoid dendritic cells (PDCs), which reside in the cornea during steady state, actively participate in the maintenance of corneal immune homeostasis, as their depletion leads to enhanced corneal leukocyte infiltration and amplified adaptive immune responses in draining lymph nodes (dLNs). Thus, in this application, we propose to evaluate the significance of PDCs in the maintenance of tolerance and the mechanisms through which PDCs contribute to corneal immune homeostasis. We will identify potential candidates through single cell sequencing of PDCs. We aim to study the role of PDCs in mediating multiple steps involved in the process of inflammation, from leukocyte recruitment to the cornea, antigen uptake and processing by antigen presenting cells, their egress to, and antigen presentation in dLNs, and priming of T cells. Additionally, we have observed that PDCs interact directly with T cells in the dLNs, and support development and stabilization of regulatory T cell (Tregs), important immunosuppressive lymphocytes. We aim to analyze the molecular mechanisms by which PDCs induce and maintain Tregs, as well as examine the clinical utility of adoptive transfer of PDC- induced Tregs in infectious keratitis, dry eye disease and corneal transplantation. We also propose to study the feasibility, efficacy, and potential local and systemic side effects of local adoptive transfer of PDCs to the cornea for the treatment of immune and inflammatory diseases. Next, we aim to evaluate therapeutic efficacy of local adoptive transfer of PDCs or application of PDC secretome in limiting clinical severity of the disease, infiltration of leukocytes, disease progression, and complications in models of dry eye disease and herpes simplex keratitis. This application proposes a paradigm shift on how PDCs modulate immunity, and could result in the introduction of new immunomodulatory therapeutic avenues for ocular as well as systemic inflammatory, autoimmune, alloimmune and infectious diseases.

概括角膜是少数享有免疫特权的组织之一，然而，角膜免疫特权是不是绝对的。在许多角膜疾病中，包括感染性角膜炎、干眼病和角膜损伤、浸润白细胞可加速疾病进展。我们的初步结果表明浆细胞样树突状细胞（PDC）在稳态时驻留在角膜中，积极参与维持角膜免疫稳态，因为它们的消耗会导致角膜增强引流淋巴结（dLN）中白细胞浸润和适应性免疫反应增强。因此，在在此应用中，我们建议评估 PDC 在维持耐受性和 PDC 促进角膜免疫稳态的机制。我们将确定通过 PDC 的单细胞测序获得潜在的候选者。我们的目标是研究 PDC 在介导炎症过程中涉及的多个步骤，从白细胞募集到角膜、抗原呈递细胞的抗原摄取和加工、它们的出口和抗原 dLN 中的呈递和 T 细胞的启动。此外，我们观察到 PDC 直接相互作用与 dLN 中的 T 细胞一起，支持调节性 T 细胞 (Treg) 的发育和稳定，重要的免疫抑制淋巴细胞。我们的目标是分析分子机制 PDC 诱导和维持 Tregs，并检查 PDC 过继转移的临床效用在感染性角膜炎、干眼病和角膜移植中诱导Tregs。我们还建议研究当地收养转移的可行性、有效性以及潜在的局部和系统副作用将 PDC 植入角膜，用于治疗免疫和炎症性疾病。接下来，我们的目标是评估 PDC局部过继转移或PDC分泌组应用限制临床的治疗效果模型中疾病的严重程度、白细胞浸润、疾病进展和并发症干眼病和单纯疱疹性角膜炎。该应用提出了 PDC 如何进行范式转变调节免疫力，并可能导致新的免疫调节疗法的引入眼部以及全身炎症、自身免疫、同种免疫和传染病的途径。