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.

摘要 角膜是少数享有免疫豁免权的组织之一，然而，角膜免疫豁免权是 不是绝对的。在许多角膜疾病中，包括传染性角膜炎、干眼病和角膜 损伤、白细胞的渗入会加速疾病的进展。我们的初步结果表明 稳定状态下驻留在角膜中的浆细胞样树突状细胞(PDCs)积极参与 在维持角膜免疫动态平衡方面，因为它们的耗尽导致角膜增强 引流淋巴结(DLN)中的白细胞浸润和放大的获得性免疫反应。因此，在 在这一应用中，我们建议评估PDCs在维持耐受性和 PDCs促进角膜免疫动态平衡的机制。我们将确定 通过对PDCs的单细胞测序获得潜在的候选者。我们的目标是研究PDC在 调节炎症过程中的多个步骤，从白细胞募集到 角膜，抗原提呈细胞的抗原摄取和处理，它们的出口和抗原 在DLN中的呈现，以及T细胞的启动。此外，我们还观察到PDC直接相互作用 在DLN中有T细胞，并支持调节性T细胞(Tregs)的发育和稳定， 重要的免疫抑制淋巴细胞。我们的目标是分析其分子机制 PDC诱导和维持Tregs，以及检测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 研究就地收养转移的可行性、有效性以及潜在的局部和全身副作用。 PDCs到角膜治疗免疫性和炎症性疾病。接下来，我们的目标是评估 局部过继转移PDCs或应用PDC分泌组限制临床的疗效 模型中疾病的严重性、白细胞的渗透、疾病的进展和并发症 干眼症和单纯疱疹病毒性角膜炎。此应用程序提出了PDC的范式转变 调节免疫，并可能导致新的免疫调节疗法的引入 眼科和全身炎症、自身免疫、同种免疫和传染病的途径。