抗肿瘤坏死因子-α抗体对脑心肌炎病毒诱导的小鼠病毒性心肌炎模型的治疗作用。

Therapeutic effect of anti-tumor necrosis factor-alpha antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus.

作者信息

Yamada T, Matsumori A, Sasayama S

机构信息

Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.

出版信息

Circulation. 1994 Feb;89(2):846-51. doi: 10.1161/01.cir.89.2.846.

DOI:10.1161/01.cir.89.2.846

PMID:8313574

Abstract

BACKGROUND

Tumor necrosis factor-alpha (TNF-alpha) has been reported to have an antiviral effect in vitro; however, its in vivo effect remains to be clarified.

METHODS AND RESULTS

To investigate the role of TNF-alpha in viral myocarditis using a murine model induced by encephalomyocarditis virus (EMCV), we evaluated (1) plasma TNF-alpha levels by enzyme-linked immunosorbent assay (ELISA), (2) the effect of recombinant human TNF-alpha for its possible antiviral effect in vivo, and (3) the effect of anti-murine TNF-alpha monoclonal antibody (mAb) in vivo. Four-week-old DBA/2 mice were inoculated intraperitoneally with EMCV (day 0). Mice were injected intravenously daily with 1 microgram of TNF-alpha or 2 x 10(3) units of anti-TNF-alpha mAb starting on day -1, day 0, or day 1 until day 2 (TNF-alpha study) or day 4 (anti-TNF-alpha mAb study). A portion of the mice were killed on day 5 (protocol 1); their hearts were removed, and plaque assays were performed to demonstrate the myocardial virus content. The remaining mice were killed on day 14 (protocol 2); myocardial lesions were examined histopathologically in terms of severity, and their survival rates were determined. Plasma TNF-alpha concentration was elevated in the blood of infected mice compared with uninfected mice 3, 5, and 7 days after virus inoculation. The myocardial virus content was higher in the TNF-alpha-treated group than in the control group. Histopathological analysis revealed that myocardial necrosis and cellular infiltration were more prominent in the TNF-alpha group than in the control group. The anti-TNF-alpha mAb improved survival and myocardial lesions when its treatment was started 1 day before virus inoculation. However, it showed no therapeutic effect when administered simultaneously with the inoculation or on day 1.

CONCLUSIONS

TNF-alpha may play an important role in the very early stage of the immune response, and anti-TNF-alpha mAb may prevent the early pathway of acute viral myocarditis.

摘要

背景

据报道，肿瘤坏死因子-α（TNF-α）在体外具有抗病毒作用；然而，其体内作用仍有待阐明。

方法与结果

为了利用脑心肌炎病毒（EMCV）诱导的小鼠模型研究TNF-α在病毒性心肌炎中的作用，我们评估了：（1）通过酶联免疫吸附测定（ELISA）检测血浆TNF-α水平；（2）重组人TNF-α在体内可能的抗病毒作用；（3）抗小鼠TNF-α单克隆抗体（mAb）在体内的作用。4周龄的DBA/2小鼠腹腔注射EMCV（第0天）。从第-1天、第0天或第1天开始，每天静脉注射1微克TNF-α或2×10³单位抗TNF-α mAb，持续至第2天（TNF-α研究）或第4天（抗TNF-α mAb研究）。部分小鼠在第5天处死（方案1）；取出心脏，进行蚀斑测定以确定心肌病毒含量。其余小鼠在第14天处死（方案2）；从严重程度方面对心肌病变进行组织病理学检查，并确定其存活率。与未感染小鼠相比，病毒接种后3、5和7天，感染小鼠血液中的血浆TNF-α浓度升高。TNF-α治疗组的心肌病毒含量高于对照组。组织病理学分析显示，TNF-α组的心肌坏死和细胞浸润比对照组更明显。当抗TNF-α mAb在病毒接种前1天开始治疗时，可提高存活率并改善心肌病变。然而，在接种时或第1天同时给药时，未显示出治疗效果。