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.

项目摘要 人工耳蜗植入物（CIS）为严重至深刻的感官的患者提供听觉康复 听力损失，现在可以使大量剩余低频听力的患者受益。植入功能和 CI后外国体内反应（FBR）可能对残留听力产生负面影响。尽管 重要的工作专门用于探测浸润巨噬细胞的作用，即淋巴细胞的作用 尚未被彻底审查。此外，已知抗原呈递细胞（例如，巨噬细胞）已知 通过淋巴管网络从末端器官到淋巴结动员，以呈现抗原与淋巴细胞的抗原 激活和募集淋巴细胞。耳蜗淋巴网络从未描述过。使用淋巴 记者小鼠和高度敏感的特异性示踪剂分子，用于淋巴管，我们发现了一个 耳蜗中丰富的淋巴网络。此外，在CI的鼠模型中，我们已经观察到淋巴细胞浸润 和激活增强人类研究中的发现。考虑到淋巴解剖学和 耳蜗中的淋巴细胞在理解和对抗CI中的FBR时，本研究提议研究 FBR后CI中的作用淋巴管和淋巴细胞。该项目的长期目标是调查 人工耳蜗免疫对损伤的基本基础。这项研究的目的是确定角色 炎症后CI中的淋巴管和淋巴细胞。中心假设是在人工耳蜗之后 植入（1）巨噬细胞（APC）通过淋巴网络传播以呈现抗原 淋巴细胞和（2）淋巴细胞对于CI后慢性炎性FBR是必需的。 采取以下两个目标，我们将测试我们的假设： 1）表征CI后人工耳蜗淋巴引流的病理生理变化，我们将首先建立 通过将淋巴样示踪剂注入耳蜗，耳蜗对淋巴结盆地的淋巴引流模式 淋巴记者小鼠，然后对耳蜗和头颈区域进行成像。调查人工耳蜗是否 植入导致APC的动员增加向耳蜗淋巴管，我们将进行CI手术 在淋巴记者小鼠中，确定耳蜗淋巴管中APC的密度，并与 适当的控件。 2）确定淋巴细胞是否需要炎症和异物反应，人工耳蜗 植入将在淋巴细胞不足的小鼠中进行，FBR将被定量并与 适当的控件。 成功后，这些目标将增强我们对耳蜗后免疫反应的理解 植入。除了人工耳蜗外，这些创新还将改变当前人工耳蜗范式 反应并可能导致无数内耳病理过程的新型治疗干预措施。