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Development of new quality control method for oral live vaccine using transgenic mice susceptible to poliovirus.

使用易感染脊髓灰质炎病毒的转基因小鼠开发口服活疫苗的新质量控制方法。

基本信息

批准号：
04507002
负责人：
KURATA Takeshi
金额：
$ 39.49万
依托单位：
National Institute of Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04507002/
关键词：
Poliovirus PVR Transgenic mice レセプターワクチン検定

项目摘要

Transgenic mice (Tg mice) carrying the human poliovirus receptor gene were susceptible to poliovirus infection showing paralysis of extremities. The pathological findings of paralytic mice were quite similar to the neuropathological changes in humans died of poliomyelitis. In this study, neuropathological changes in Tg mice inoculated with virulent strain, vaccine and field-isolates were compared to the conventional neurovirulence test using monkeys whether Tg mice are useful instead of monkeys for neurovirulence test of poliovirus vaccine.(1) Neurovirulence was observed parallel to the virus titer.(2) Intra-spinal cord administration route was established.(3) Intracerebral in oculation of field-isolates resulted in clear histopathological changes (inflammatory cell infiltration, degeneration of neurones, especially atrophy) with viral antigen in paralytic Tg mice. But in Tg mice without clinical signs no pathological changes were revealed.(4) Lesion score in monkeys was compared in Tg 21 mice by PD50 method using poliovirus type 1 and 3, and high correlation was observed reproductively and this measurement system is more precise than conventional monkey system.(5) In neurovirulence test of Tg 21 mice, high correlation was seen between in vitro poliovirus marker test and rct marker in monkeys.(6) The above results in Tg 21 mice reflects more objectively than in test using monkeys from the points of neurovirulence.(7) Stable supplying system of Tg mice was established.

携带人脊髓灰质炎病毒受体基因的转基因小鼠（Tg小鼠）对脊髓灰质炎病毒感染易感，表现为四肢瘫痪。麻痹小鼠的病理学表现与人脊髓灰质炎死亡后的神经病理学改变十分相似。本研究比较了Tg小鼠接种强毒株、疫苗和野毒株后的神经病理学变化，并与传统的猴神经毒力试验进行比较，以探讨Tg小鼠是否可以代替猴进行脊髓灰质炎疫苗的神经毒力试验。(1)观察到神经毒力与病毒滴度平行。(2)建立脊髓内给药途径。(3)脑内接种的外地分离株导致明确的组织病理学变化（炎性细胞浸润，神经元变性，特别是萎缩）与病毒抗原在麻痹的Tg小鼠。但在无临床症状的Tg小鼠中，未显示任何病理变化。(4)使用1型和3型脊髓灰质炎病毒，通过PD 50方法在Tg 21小鼠中比较猴中的病变评分，可重复观察到高度相关性，该测量系统比常规猴系统更精确。(5)在Tg 21小鼠神经毒力试验中，脊髓灰质炎病毒体外标记物试验与猴rct标记物之间存在高度相关性。(6)从神经毒力的角度来看，Tg 21小鼠的上述结果比猴试验的结果更客观。(7)建立了稳定的转基因小鼠营养供应体系。