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.

项目总结