Role of lymphocytes and newly discovered cochlear lymphatics in the foreign body response following cochlear implantation

淋巴细胞和新发现的耳蜗淋巴管在人工耳蜗植入后异物反应中的作用

• 批准号: 10537164
• 负责人: Muhammad Taifur Rahman
• 金额: $ 7.11万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537164
• 关键词: Acoustics; Adult; Anatomy; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Blood Vessels; Cavia; Cells; Chronic; Cochlea; Cochlear Implants; Cochlear implant procedure; Contralateral; Data; Dexamethasone; Foreign Bodies; Foundations; Frequencies; Functional disorder; Future; Goals; Hair Cells; Head and neck structure; Hearing; Human; Image; Immune; Immune response; Immunosuppressive Agents; Implant; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Labyrinth; Lead; Lymphatic; Lymphatic System; Lymphocyte; Mus; Myofibroblast; Neuroglia; Neurons; Operative Surgical Procedures; Organ; Outcome; Pathologic Processes; Patients; Pattern; Perilymph; Persons; Play; Public Health; Quality of life; Rag1 Mouse; Reporter; Research; Residual state; Role; Scala Tympani; Secondary to; Sensorineural Hearing Loss; Sensory; Side; Supporting Cell; T lymphocyte marker; T-Lymphocyte; Testing; Time; TimeLine; Tracer; Travel; Tumor-infiltrating immune cells; Work; animal imaging; auditory rehabilitation; base; career; cell type; density; draining lymph node; electric impedance; experimental study; implantation; improved; innovation; lymph nodes; lymphatic drainage; lymphatic imaging; lymphatic vasculature; lymphatic vessel; macrophage; mouse model; negative affect; novel therapeutic intervention; podoplanin; recruit; response; response to injury; secondary lymphoid organ

Project Summary Cochlear implants (CIs), provides auditory rehabilitation for patients with severe to profound sensorineural hearing loss and can now benefit patients with significant residual low frequency hearing. Implant function and residual hearing can be negatively affected by post-CI inflammatory foreign body response (FBR). While significant body of work has been devoted to probe the role of infiltrating macrophages, the role of lymphocytes has not been thoroughly scrutinized. Moreover, antigen presenting cells (APC e.g., macrophages) are known to mobilize from the end organ to lymph nodes via lymphatic vascular network to present antigen to lymphocytes, activate and recruit lymphocytes. A cochlear lymphatic network has never been described. Using a lymphatic reporter mouse and highly sensitive and specific tracer molecule for lymphatic vessels, we have discovered a rich lymphatic network in cochlea. Besides, in a murine model of CI, we have observed lymphocyte infiltration and activation reinforcing findings in human studies. Given the potential importance of lymphatic anatomy and lymphocytes in the cochlea in understanding and combatting the FBR in CIs, this study proposes to investigate the role lymphatics and lymphocytes in the FBR post-CI. The long-term goal of this project is to investigate fundamental basis of cochlear immune responses to damage. The objective of this study is to determine the role of lymphatics and lymphocytes in the inflammatory FBR post-CI. The central hypothesis is, following cochlear implantation (1) macrophages (APCs) travel through the lymphatic network to present antigens to the lymphocytes and that (2) lymphocytes are necessary for chronic inflammatory FBR post-CI. Undertaking the following two aims, we will test our hypotheses: 1) To characterize the pathophysiological changes in cochlear lymphatic drainage post-CI, we will first establish the pattern of lymphatic drainage of cochlea to lymph node basin by injecting lymphatic tracers into cochlea of lymphatic reporter mice followed by imaging of cochlea and head neck region. To investigate whether cochlear implantation results in increased mobilization of APCs to cochlear lymphatic vessels, we will perform CI surgery in lymphatic reporter mice, determine the density of APCs within cochlear lymphatics, and compare with appropriate controls. 2) To determine whether lymphocytes are necessary for the inflammation and foreign body response, cochlear implantation will be performed in lymphocyte deficient mice, FBR will be quantified and compared with appropriate controls. When successful, these aims will enhance our understanding of the immune response following cochlear implantation. Beyond cochlear implantation, these innovations will shift the current paradigm of cochlear immune response and likely lead to novel therapeutic interventions for a myriad of inner ear pathologic processes.

项目概要 人工耳蜗 (CI) 为重度至极重度感音神经性患者提供听觉康复 听力损失，现在可以使具有明显残余低频听力的患者受益。种植体功能和 CI 后炎症异物反应 (FBR) 可能会对残余听力产生负面影响。尽管 大量的工作致力于探索浸润巨噬细胞的作用、淋巴细胞的作用 尚未经过彻底审查。此外，已知抗原呈递细胞（APC，例如巨噬细胞） 通过淋巴血管网络从终末器官动员到淋巴结，将抗原呈递给淋巴细胞， 激活并募集淋巴细胞。耳蜗淋巴网络从未被描述过。使用淋巴管 报告小鼠和高度敏感和特异性的淋巴管示踪分子，我们发现了一种 耳蜗内有丰富的淋巴网络。此外，在CI小鼠模型中，我们观察到淋巴细胞浸润 以及人类研究中的激活强化发现。鉴于淋巴解剖学的潜在重要性和 耳蜗中的淋巴细胞在理解和对抗 CI 中的 FBR 中的作用，本研究旨在调查 淋巴管和淋巴细胞在 CI 后 FBR 中的作用。该项目的长期目标是调查 耳蜗对损伤的免疫反应的基本基础。本研究的目的是确定角色 CI 后炎症性 FBR 中淋巴管和淋巴细胞的数量。中心假设是，遵循耳蜗 植入 (1) 巨噬细胞 (APC) 穿过淋巴网络，将抗原呈递给 (2) 淋巴细胞对于 CI 后慢性炎症 FBR 是必需的。 为了实现以下两个目标，我们将检验我们的假设： 1) 为了表征 CI 后耳蜗淋巴引流的病理生理变化，我们首先建立 通过将淋巴示踪剂注入耳蜗，将耳蜗淋巴引流至淋巴结盆地的模式 淋巴报告小鼠，随后对耳蜗和头颈区域进行成像。调查是否有耳蜗 植入导致 APC 向耳蜗淋巴管的动员增加，我们将进行 CI 手术 在淋巴报告小鼠中，测定耳蜗淋巴管内 APC 的密度，并与 适当的控制。 2) 为了确定淋巴细胞是否是炎症和异物反应所必需的，耳蜗 植入将在淋巴细胞缺陷小鼠中进行，FBR将被量化并与 适当的控制。 如果成功，这些目标将增强我们对人工耳蜗术后免疫反应的理解 植入。除了人工耳蜗植入之外，这些创新还将改变当前的耳蜗免疫模式 反应并可能导致针对多种内耳病理过程的新颖的治疗干预措施。