基于泛素-蛋白酶体系统的细胞内原虫DNA疫苗的研制-猫眼课题宝

基于泛素-蛋白酶体系统的细胞内原虫DNA疫苗的研制

批准号：

15390136

负责人：

HIMENO Kunisuke

金额：

$9.73万

依托单位：

KYUSHU UNIVERSITY

依托单位国家：

日本

项目类别：

Grant-in-Aid for Scientific Research (B)

财政年份：

2003

资助国家：

日本

项目状态：

已结题

起止时间：

2003 至 2005

来源：

https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390136/

关键词：

intracellular protozoa DNA vaccine gene gun ubiquitin ubiquitin-proteasome CD8^+ T cell proteasome KO mice proteasome inhibitor 細胞内寄生原虫ユビキチンプロテアソーム系トキソプラズマ SAG-1 ユビキチン融合遺伝子 PA28ノックアウトマウス

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项目成果

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中文摘要

翻译

细胞内原生动物弓形虫(T.Gondii)是世界各地免疫缺陷患者群体中的一种主要的条件致病菌。在候选疫苗中，SAG1蛋白的特性最好。这个30 kDa的蛋白是弓形虫速殖子的主要表面抗原，在弓形虫株中高度保守，在人类中诱导高水平的抗体，并被所有感染者的血清样本识别。CD8~+T细胞在抵御强毒力弓形虫RH株的免疫中起着重要作用。已经确定了SAG1中包含的一些CD8~+CTL表位。然而，大多数疫苗试验，包括DNA疫苗，除了对培养和减毒株外，对高毒力的RH株都是失败的。在本研究中，我们构建了编码泛素化的SAG1的疫苗载体，该载体可能经过“泛素-蛋白酶体途径”的处理，然后被引导到MHC I类分子，从而激活SAG1特异性的CD8^+T细胞。用嵌合DNA免疫的小鼠对SAG1特异性CD8^+T细胞介导的弓形虫具有很强的保护性，而单独接种SAG1基因的小鼠则没有。增强的免疫力依赖于SAG1的泛素化，使其能够被蛋白酶体途径有效地处理，从而有效地诱导特定的CD8^+T细胞。免疫依赖于免疫蛋白酶体LMP7，但不依赖蛋白酶体激活剂PA28a/b。

英文摘要

The intracellular protozoan Toxoplasma gondii (T.gondii) is a major opportunistic pathogen in the immunocompromized patient population worldwide. Among the vaccine candidates, the SAG1 protein is the best characterized. This 30-kDa protein is the major surface antigen of T.gondii tachyzoites, is highly conserved in T.gondii strains, inducing high antibody levels in humans, and is recognized by all the serum samples from infected subjects. CD8^+ T cells play an essential role in the protection against a highly virulent RH strain of T.gondii. Some CD8^+ CTL epitopes included in the SAG1 had been defined. However, most vaccine trials including DNA vaccine have resulted in failure agaist the high virulent RH strain except against the cultured and attenuated strain. In the present study, we constructed the vaccine vector encoding ubiquitinated SAG1 which is expected to be processed by "ubiquitin-proteasome pathway" and then be led to MHC class I molecules, resulting in the activation of SAG1-specific CD8^+ T cells.Mice immunized with the chimeric DNA developed potent protective immunity against Toxoplasma mediated by SAG1-specific CD8^+ T cells, while mice immunized with SAG1 gene alone did not. The enhanced immunity was dependent on the ubiquitination of SAG1 that enabled it to be efficiently processed by the proteasome pathway resulting in efficient induction of specific CD8^+T cells. The immunity was dependent on immunoproteasome LMP7 but independent on PA28a/b, a proteasome activator.

期刊论文(50)

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会议论文

Cathepsin L is crucial for Th1-type immune response during Leishmania major infection.

组织蛋白酶 L 对于利什曼原虫重大感染期间的 Th1 型免疫反应至关重要。

DOI： --

发表时间： 2004

期刊：

Microbes and Infection Apr 6(5)

影响因子： --

作者：

[Toyooka, K., et al., Kaneko O, Yano K, Kaneko 0, Yano K, Arakawa T, Sawasaki T, Arakawa T, Sawasaki T, Arakawa T, Kaneko O, Rungruang T, Sattabongkot J, Li F, Li F, Ling IT, Tsuboi T, Li F, Kongkasuriyachai D, Win TT, Duan X.et al., Ishii K. et al., Duan X.et al., Ishii K. et al., Duan X.et al., Ishii K. et al., Hisaeda H. et al., Zhang M. et al., Hisaeda H. et al., Hisaeda H. et al., Zhang M. et al., Hisaeda H. et al., Hisaeda H. et al., Zhang M. et al., Zhang M. et al., Hisaeda H. et al., Okamoto M. et al., Obata C. et al., Onishi K. et al., Yamanaka A. et al., Zhang M. et al., Li Y.et al., Hisaeda H. et al., Okamoto M. et al., Obata C. et al., Onishi K. et al.]

通讯作者： Onishi K. et al.

The ubiquitin-proteasome system plays an essential role in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8^+T cells.

泛素-蛋白酶体系统在将APC中表达的8聚体CTL表位呈递给相应的CD8+T细胞方面发挥重要作用。

DOI： --

发表时间： 2006

期刊：

Int.Immunol. (in press)

影响因子： --

作者：

[Duan X.et al., Ishii K. et al., Duan X.et al., Ishii K. et al., Duan X.et al.]

通讯作者： Duan X.et al.

Hyperproduction of proinflammatory Cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis