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.

总结 角膜是享有免疫豁免的少数组织之一，然而，角膜免疫豁免是免疫豁免的一部分。 不是绝对的。许多角膜疾病，包括传染性角膜炎、干眼病和角膜炎 损伤，浸润性白细胞可以促进疾病进展。我们的初步结果表明， 浆细胞样树突状细胞（PDCs），在稳定状态下驻留在角膜中，积极参与 在维持角膜免疫稳态中，由于它们的消耗导致增强的角膜免疫， 引流淋巴结（dLN）中的白细胞浸润和扩增的适应性免疫应答。因此在 本申请中，我们建议评估PDCs在维持耐受性方面的意义， PDCs促进角膜免疫稳态的机制。我们将确定 通过对PDC的单细胞测序确定潜在候选物。我们的目标是研究PDCs在以下方面的作用： 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 在dLN中的呈递和T细胞的引发。此外，我们观察到PDCs直接相互作用， 与dLN中的T细胞，并支持调节性T细胞（TCLs）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， PDCs诱导和维持THP，以及检查PDCs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TdR。我们亦建议 研究局部过继转移的可行性、有效性和潜在的局部和全身副作用， 将PDCs移植到角膜，用于治疗免疫性和炎症性疾病。接下来，我们将评估 局部过继转移PDC或应用PDC分泌体限制临床疗效 疾病的严重程度、白细胞浸润、疾病进展和模型中的并发症 干眼病和单纯疱疹性角膜炎。该应用程序提出了一个关于PDC如何 调节免疫力，并可能导致引入新的免疫调节治疗方法， 治疗眼部和全身炎症、自身免疫、同种免疫和感染性疾病的途径。