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

项目摘要 人工耳蜗术为重度至深部感觉神经病患者提供听觉康复。 听力损失，现在可以使有显著残余低频听力的患者受益。植入功能和 脑梗塞后炎症性异物反应(FBR)对残余听力有负面影响。而当 大量的工作一直致力于探索渗透巨噬细胞的作用，淋巴细胞的作用 还没有得到彻底的审查。此外，已知抗原提呈细胞(APC，如巨噬细胞) 通过淋巴管网从末端器官动员到淋巴结，将抗原呈递给淋巴细胞， 激活和招募淋巴细胞。耳蜗淋巴网从来没有被描述过。使用淋巴管 报道小鼠和高度敏感和特异的淋巴管示踪分子，我们发现了一种 耳蜗内有丰富的淋巴网。此外，在脑梗塞的小鼠模型中，我们观察到淋巴细胞的渗透。 而激活则加强了人体研究的发现。考虑到淋巴解剖的潜在重要性 耳蜗内淋巴细胞在理解和对抗顺铂FBR中的作用，本研究拟探讨 淋巴管和淋巴细胞在脑梗塞后FBR中的作用。这个项目的长期目标是调查 耳蜗免疫反应损伤的基本基础。这项研究的目的是确定 脑梗塞后炎性FBR中淋巴管和淋巴细胞的变化。中心假说是，在耳蜗线之后 植入(1)巨噬细胞(APC)通过淋巴网络将抗原递送给 淋巴细胞和(2)淋巴细胞是脑梗塞后慢性炎症性FBR所必需的。 为了实现以下两个目标，我们将检验我们的假设： 1)为了描述CI后耳蜗管引流的病理生理变化，我们首先建立 耳蜗腔内注射淋巴示踪剂对耳蜗区淋巴引流规律的研究 淋巴报告小鼠，随后对耳蜗区和头颈区进行成像。调查是否有人工耳蜗术 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)确定炎症和异物反应是否需要淋巴细胞。 将在淋巴细胞缺陷小鼠中进行植入，FBR将被量化并与 适当的控制。 一旦成功，这些目标将加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，这些创新将改变目前的耳蜗免疫模式 反应，并可能导致对无数内耳病理过程的新的治疗干预。

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.