Induction of protective immunity against malaria by MSP1/hsc70 fusion protein vaccine

MSP1/hsc70融合蛋白疫苗诱导抗疟疾保护性免疫

• 批准号: 12670234
• 负责人: YUI Katsuyuki
• 金额: $ 2.5万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670234/
• 关键词: Malaria; vaccine; immunity; MSP1; stress protein; adjuvant; Protozoa; infection; アジュバント; 抗体; 抗原; 防御

We have developed a method to induce CD4 and CDS specific immune responses by immunizing mice with a particular antigen as a fusion partner of mouse heat-shock cognate protein 70 (hsc70). We used this strategy to induce protective immunity against malaria sporozoite infection. We generated a recombinant protein of MSP1 fused to hsc70 (MSP1/hsc70) and studied whether it could induce protective immunity against liver stage P. yoelii, since we found that MSP1 is expressed during liver stage of P. yoelii life cycle. The immunization of mice with MSP1/hsc70 without any additional adjuvant induced strong specific antibody responses and IFN-y production. When the immunized mice were challenged with P. yoelii sporozoites, the onset of parasitemia delayed a few days when compared with naive mice or mice immunized with hsc70 alone, suggesting the induction of protective immune responses against liver stage malaria. To confirm the MSP1-specific protective immune responses against exoerythrocytic forms of malaria infection, we performed RT-PCR analysis of P. yoelii-specific rRNA in the infected liver. The level of P. yoelii was reduced in mice immunized with this fusion protein, but not in mice immunized with hsc70 alone, suggesting that MSP1-specific protective immunity is effective at liver stage malaria. This protective immunity was transferred into naive mice by spleen cells or liver lymphocytes of immune mice but not by antiserum, indicating that the protection is mediated by cellular mechanisms. Finally, the vaccine-induced protection was observed in C57BL/6, A/J, BALB/c and C3H mice suggesting that MSP1-specific protective immunity at the exoerythrocytic stage can be induced in animals over a wide range of genetic backgrounds.

我们已经开发了一种方法，通过用特定的抗原作为小鼠热休克同源蛋白70（hsc 70）的融合伴侣免疫小鼠来诱导CD 4和CDS特异性免疫应答。我们用这种策略来诱导针对疟疾子孢子感染的保护性免疫。我们构建了MSP 1与hsc 70融合的重组蛋白（MSP 1/hsc 70），并研究了其是否能诱导针对肝期约氏疟原虫的保护性免疫。用MSP 1/hsc 70免疫小鼠而没有任何额外的佐剂诱导强烈的特异性抗体应答和IFN-γ产生。当用约氏疟原虫子孢子攻击免疫小鼠时，与幼稚小鼠或单独用hsc 70免疫的小鼠相比，寄生虫血症的发作延迟了几天，表明诱导了针对肝期疟疾的保护性免疫应答。为了证实MSP 1特异性保护性免疫应答对抗红细胞外型疟疾感染，我们对感染肝脏中的约氏疟原虫特异性rRNA进行了RT-PCR分析。在用该融合蛋白免疫的小鼠中，约氏疟原虫的水平降低，但在单独用hsc 70免疫的小鼠中没有降低，这表明MSP 1特异性保护性免疫在肝期疟疾中是有效的。这种保护性免疫通过免疫小鼠的脾细胞或肝淋巴细胞而不是通过抗血清转移到幼稚小鼠中，表明这种保护是由细胞机制介导的。最后，在C57 BL/6、A/J、BALB/c和C3 H小鼠中观察到疫苗诱导的保护，表明在红细胞外期的MSP 1特异性保护性免疫可以在广泛的遗传背景的动物中诱导。

项目成果

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I.Sano 等人：“促炎性细胞因子抑制剂延长大鼠同种异体心脏移植物的存活”J.Heart and lung Transpl.（正在出版）。

Sano I., Takahashi T., Koji ., Udono H., Yui K., Ayabe H.: "Prolonged survival of rat cardiac allograft with proinflammatory cytokine inhibitor"J. Heart Lung Transplant.. 20 (5). 538-589 (2001)

Sano I.、Takahashi T.、Koji .、Udono H.、Yui K.、Ayabe H.：“使用促炎细胞因子抑制剂延长大鼠同种异体心脏移植物的存活”J。

I.Sano et al.: "Prolonged survival of rat cardiac allograft by proinflamatory cytokine inhibitor"J. Heart and Lung Transpl.. 20(5). 583-589 (2001)

I.Sano 等人：“促炎细胞因子抑制剂延长大鼠同种异体心脏移植物的存活”J.

S.Murata et al.: "Immunoproteasome assembly and antigen presentation in mice lacking both PA28α and PA28β"EMBOJ. 20(21). 5898-5907 (2001)

S.Murata 等人：“缺乏 PA28α 和 PA28β 的小鼠中的免疫蛋白酶体组装和抗原呈递”EMBOJ 20(21) (2001)。

Udono, H., T. Yamano, Y., Kawabata, M., Uedaj and K. Yui.: "Generation of cytotoxic T lymphocytes by MHC class I ligand fused to heat shock cognate protein 70"International Immunol.. 13 (10). 1233-1242 (2001)

Udono, H.、T. Yamano, Y.、Kawabata, M.、Uedaj 和 K. Yui.：“通过与热休克同源蛋白 70 融合的 MHC I 类配体生成细胞毒性 T 淋巴细胞”国际免疫学杂志 13 (10