Mechanisms of sensorineural hearing loss and its treatments for prevention and cure in animal models

本研究在动物模型上探讨了感音神经性听力损失的发病机制及防治方法。我们首先利用移植物抗宿主病的动物模型证明了供体T细胞浸润到关节周围区域的增殖细胞的存在。这些发现表明，体循环中的免疫活性细胞通过血迷路和血内淋巴管浸润到内淋巴囊或内耳，并作为免疫反应的局部增殖。它们还表明，梅尼埃氏病是一种器官特异性自身免疫性疾病，类似于慢性甲状腺炎和青少年糖尿病。我们还指出，老年性耳聋（与年龄相关的听力损失）在加速衰老的动物模型中加速，包括免疫功能受损时与年龄相关的免疫功能障碍和听力损失的加速。这些结果支持了我们关于内耳全身免疫系统和局部免疫系统之间关系的理论，也表明某些类型的内耳疾病不是由内耳缺陷引起的，而是由管理全身免疫系统的造血干细胞（hsc）和源自hsc的免疫能力细胞的缺陷引起的。这些发现提示我们可以利用骨髓移植（BMT）和放射治疗，通过正常供体细胞重建宿主免疫能力细胞和全身免疫系统以及宿主造血干细胞，来预防或治疗年龄相关性听力损失或自身免疫性听力损失。本研究结果提示了BMT对听力损失的预防或治疗作用，并证实了某些类型的内耳疾病是由造血干细胞功能障碍引起的。如果是这样的话，同种异体骨髓移植（用正常造血干细胞替代异常造血干细胞，重建宿主的正常免疫系统）或使用转基因骨髓细胞的自体骨髓移植（自体骨髓移植）都可能成为治疗包括感音神经性听力损失在内的内耳疾病的新策略。少

In the present study, we have investigated mechanisms of sensorineural hearing loss and its treatments for prevention and cure in animal models. We have first demonstrated using an animalmodel for graft-versus-host disease the existence of proliferating cells in the donor T cells infiltrating the perisaccular region. These findings suggest that immunocompetent cells in the systemic circulation infiltrate the endolymphatic sac or inner ear through the blood-labyrinthine and blood-endolymphatic barrlers and proliferate locally as a consequence of the immune response. They also indicate that Meniere's disease is an organ-specific autoimmune disease and similar to chronic thyroiditis and juvenile diabetic mellitus. We have also indicated that presbycusus (age-related hearing loss) is accelerated in an animal model for accelerated senescence including the age-related acceleraation of both immunological dysfunction and hearing loss when the immune function is impaired as a consequence of bre … More eding the animal under pathogenic environment. These results support our theory of relation between the systemic immune system and local immune system in the inner ear and also indicate that some types of inner ear diseases do not result from defects in the inner ear but do from defects in the hematopoletic stem cells (HSCs) and immunocompetent cells derived from the HSCs, which manage the systemic immune system.These findings have prompted us to prevent or cure the age-related hearing loss or autoimmune hearing loss using bone marrow transplantation (BMT) followed by irradiation, which reconstitute the host immunocompetent cells and systemic immune system as well as host HSCs by the normal donor cells. The results of study indicate preventive or curative effect of BMT upon those hearing losses and confirme that some types of inner ear diseases cause by dysfunction of HSCs. If this is the case, either allogeneic BMT, which replaces abnormal HSCs with normal HSCs and reconstructs a normal immune system in the hosts, or autologous BMT using genetically modified bone marrow cells, could become a new strategy for the treatment of inner ear disease including sensorineural hearing loss. Less