Development of Pharmacokinetic and Safety Assessment of in vivo Virus Infection and Vaccine Therapy

体内病毒感染和疫苗治疗的药代动力学和安全性评估的进展

基本信息

批准号：
07557174
负责人：
TERASAKI Tetsuya
金额：
$ 6.14万
依托单位：
Tohoku University (1996)The University of Tokyo (1995)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557174/
关键词：
Poliovirus Virus receptor Pharmacokinetics Vaccine Brain Organ tropism Blood-brain barrier :Transgenic mouse

项目摘要

It is significantly important subjict to elucidate the mechanism of organ tropism of virus infection in gene and vaccine therapy. In the present study, poliovirus, known to be the causative agent of poliomyelitis, has been selected as a model virus to develop the safety assesement of vaccine therapy and to predict the in vivo virus infection in the body based on pharmacokinetic analysis. The transgenic (Tg) mice carrying the human gene for poliovirus receptor (PVR), which is susceptible to intraven ously (IV) -inoculated poliovirus, has been used for the in vivo enfection studies. To know cotribution of PVR to tissue distribution and BBB permeability of IV-inoculated polioviruses, these processes were investigated and compared between the Tg mice and non-Tg mice. Distribution profile of IV-inoculated poliovirus in various tissues of the Tg mice is similar to that in non-Tg mice, suggesting that tissue distribution of IV-inoculated virus is independent of the transgene for PVR.Amount of poliovirus transfered to the CNS demonstrates an existence of specific invasion pathway for the virus to the CNS.The viruses, regardless of whether the virulent and attenuated strain, seem to accumulate at a constant rate of approximately 0.2ul/min/g brain. Similar phenomena were observed when the viruses were inoculated into non-Tg mice. These data suggest that polioviruses permeate the BBB at a fairly high rate, independently of PVR and verus strains. If it is also true in humans, circulating poliovirus including the Sabin vaccine strains easily invade the human CNS.Some molecules other than PVR may be involved in the BBB permeability of poliovirus.

阐明基因和疫苗疗法中病毒感染器官向性能的机理是非常重要的。在本研究中，已选择脊髓灰质炎病毒是脊髓灰质炎的病毒，以开发疫苗疗法的安全性调节，并根据药物动力学分析预测体内体内病毒感染。在体内研究研究中，已使用携带人类基因的脊髓灰质炎病毒受体（PVR）的转基因（TG）小鼠（PVR）（IV）受控的脊髓灰质炎病毒。为了了解PVR对IV接种脊髓灰质炎病毒的组织分布和BBB渗透性的共同侵蚀，研究了这些过程并比较了TG小鼠和非TG小鼠。 TG小鼠各种组织中IV接种脊髓灰质炎病毒的分布分布与非TG小鼠的分布相似，这表明IV接种病毒的组织分布与PVR的转基因独立恒定速率约为0.2ul/min/g脑。当将病毒接种到非TG小鼠中时，观察到类似的现象。这些数据表明，脊髓灰质炎病毒以相当高的速度渗透到BBB，而与PVR和Verus菌株无关。如果在人类中也是如此，包括萨宾疫苗菌株在内的循环脊髓灰质炎病毒很容易侵入人类CN。除PVR以外的其他分子可能参与了脊髓灰质炎病毒的BBB渗透性。