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

• 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
• 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

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 角膜是享受免疫特权的少数组织之一，但是，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，浸润的白细胞可以提高疾病的进展。我们的初步结果表明 静态状态下居住在角膜中的浆细胞类动物树突状细胞（PDC）积极参与 在维持角膜免疫稳态的过程中，由于它们的耗竭导致角膜增强 排水淋巴结（DLNS）中的白细胞浸润和放大的适应性免疫反应。因此，在 该应用程序，我们建议评估PDC在维持耐受性和 PDC有助于角膜免疫稳态的机制。我们将确定 通过PDC的单细胞测序的潜在候选物。我们旨在研究PDC在 从白细胞募集到炎症过程中涉及的多个步骤 角膜，抗原摄取和抗原呈递细胞的加工，其出口到和抗原 DLN中的呈现和T细胞的启动。此外，我们观察到PDC直接相互作用 DLN中的T细胞并支持调节性T细胞（Tregs）的发展和稳定， 重要的免疫抑制淋巴细胞。我们旨在分析分子机制 PDC诱导和维持Treg，并检查PDC-的收养转移的临床实用性 感染性角膜炎，干眼病和角膜移植引起的Treg。我们还建议 研究局部收养转移的可行性，功效以及潜在的局部和系统副作用 PDC到角膜以治疗免疫和炎症性疾病。接下来，我们的目标是评估 PDC的局部收养转移或PDC分泌组的治疗功效在限制临床方面 疾病的严重程度，白细胞浸润，疾病进展以及并发症 干眼病和单纯疱疹性角膜炎。该申请提出了对PDC的范式转变 调节免疫力，并可能导致新的免疫调节治疗 眼部以及全身性炎症，自身免疫，同种免疫和传染病的途径。