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MECHANISMS OF PROTECTION AGAINST RETROVIRAL INFECTIONS INDUCED WITH A SINGLE-EPITOPE CD4^+ T-CELL VACCINE

单表位 CD4^ T 细胞疫苗诱导的逆转录病毒感染的保护机制

基本信息

批准号：
11670307
负责人：
MIYAZAWA Masaaki
金额：
$ 2.3万
依托单位：
KINKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

We have previously shown that immunization with a synthetic peptide that contains a single CD4^+ T-cell epitope protects highly susceptible mice against immunosuppressive Friend retrovirus infection. Cells producing infectious Friend virus were rapidly eliminated from the spleen of mice that had been immunized with the single- epitope peptide. However, actual effector mechanisms induced through T-helper cell responses after Friend virus inoculation were unknown. When cytotoxic effector cells detected in the early phase of Friend retrovirus infection were separated based on their expression of cell surface markers, those lacking CD4 and CD8 but expressing natural killer cell markers were found to constitute the majority of effector cells that lysed Friend virus-induced leukemia cells. Depletion of natural killer cells by injecting anti-asialo GM_1 antibody did not affect the number of CD4^+ or CD8^+ T cells in the spleen, virus antigen-specific proliferative responses of CD4^+ T cells, … More or cytotoxic activity against Friend virus-induced leukemia cells exerted by CD8^+ effector cells, but completely abolished the effect of peptide immunization. Although the above enhancement of natural killer cell activity in the early stage of Friend virus infection was also observed in mice given no peptide, these results have demonstrated the importance and requirement of natural killer cells in the vaccine-induced resistance against the retroviral infection.Other sets of cell-depletion and transfer experiments also showed that CD4^+ and CD8^+ T cells were required for the vaccine-induced protection against Friend retrovirus infection, and the presence of CD4^+ T cells was absolutely required for the production, but not just class switching, of virus-neutralizing antibodies. Thus, these results clearly show that a single-epitope CD4^+ T cell vaccine induces immune resistance against Friend retrovirus infection by rapidly activating multiple effector mechanism soon after the virus infection including CD4^+ and CD8^+ cytotoxic effector cells, virus-neutralizing antibodies, and NK cells. Less

我们之前已经证明，用含有单个 CD4^+ T 细胞表位的合成肽进行免疫可以保护高度易感的小鼠免受免疫抑制性 Friend 逆转录病毒感染。产生传染性弗兰德病毒的细胞被迅速从用单表位肽免疫的小鼠的脾脏中消除。然而，接种弗兰德病毒后通过 T 辅助细胞反应诱导的实际效应机制尚不清楚。当根据细胞表面标志物的表达来分离弗兰德逆转录病毒感染早期检测到的细胞毒性效应细胞时，发现那些缺乏CD4和CD8但表达自然杀伤细胞标志物的细胞构成了裂解弗兰德病毒诱导的白血病细胞的大部分效应细胞。通过注射抗asialo GM_1抗体来消除自然杀伤细胞，并不会影响脾脏中CD4^+或CD8^+ T细胞的数量、CD4^+ T细胞的病毒抗原特异性增殖反应，或CD8^+效应细胞对Friend病毒诱导的白血病细胞发挥的细胞毒活性，但完全消除了肽免疫的效果。尽管在未给予肽的小鼠中也观察到上述在Friend病毒感染早期自然杀伤细胞活性的增强，但这些结果证明了自然杀伤细胞在疫苗诱导的针对逆转录病毒感染的抵抗力中的重要性和必要性。其他组的细胞耗竭和转移实验也表明CD4^+和CD8^+T细胞是疫苗诱导的针对Friend逆转录病毒感染的保护所必需的， CD4^+ T 细胞的存在对于病毒中和抗体的产生（而不仅仅是类别转换）是绝对必需的。因此，这些结果清楚地表明，单表位 CD4^+ T 细胞疫苗通过在病毒感染后迅速激活多种效应机制（包括 CD4^+ 和 CD8^+ 细胞毒性效应细胞、病毒中和抗体和 NK 细胞），诱导针对 Friend 逆转录病毒感染的免疫抵抗。较少的