人源轮状病毒T细胞识别及其小型猪腹泻模型的建立

发布时间：2018-01-01 00:18

本文关键词：人源轮状病毒T细胞识别及其小型猪腹泻模型的建立　出处：《第三军医大学》2006年博士论文　论文类型：学位论文

【摘要】： A组轮状病毒是造成全世界婴幼儿严重腹泻的最主要病原。最新统计资料表明,全世界5岁以下儿童每年约有1亿3千8百万患轮状病毒感染,其中约454,000-705,000例死亡(82%的死亡病例发生在发展中国家)。目前,轮状病毒尚无特效治疗药物及安全有效的预防性疫苗,对轮状病毒感染的免疫保护机制的进一步研究是当前研究的重点与难点。在小鼠轮状病毒感染模型中的大量研究表明,TCRαβ+/+CD8+T细胞在抗轮状病毒原发感染及再次感染中具有重要作用。研究发现,在无轮状病毒抗体的情况下,轮状病毒感染的成年小鼠的CD8+ T细胞可被动保护乳鼠,并且可介导重症免疫缺陷小鼠清除慢性轮状病毒感染;细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTL)缺陷小鼠(β2-microglobulin knockout mice)及其他封闭了CD8+ T细胞的小鼠清除轮状病毒感染的时间延迟1-4天;B细胞缺陷(J(H)D基因敲除)小鼠可清除轮状病毒的原发感染,封闭CD8+ T细胞后则转为慢性感染;B细胞缺陷小鼠原发感染18天后可介导几乎完全的免疫保护,6周、5个月及8个月仍能介导部分的免疫保护,但封闭CD8+T细胞后,在原发轮状病毒感染13天、18天、6周及5个月再次攻击则会转为轮状病毒慢性感染,而封闭TCRγδ+/+T细胞几乎无影响,表明TCRαβ+/+CD8+ T细胞介导了对轮状病毒再次感染的免疫保护。进一步研究显示,轮状病毒结构蛋白VP6与VP7是其CTL效应的主要靶标。VP6是轮状病毒的组抗原,其含量占轮状病毒蛋白总量的51%,同组轮状病毒VP6的氨基酸序列高度保守(87-99%);VP7是轮状病毒主要的外壳结构蛋白,约占病毒蛋白总量的30%,与此同时, VP7不但可引起极强的CTL效应,并且与轮状病毒不同血清型具有完全的交叉反应。尽管现已有猴源轮状病毒SA11(G3)及牛源轮状病毒UK(G6)的鼠源限制性CTL表位鉴定方面的报道,但均不能用于人体内轮状病毒感染中CD8+T细胞的研究。目前,CD8+T细胞在人体内轮状病毒感染中的地位与作用如何,尚不明了。至今尚未见轮状病毒HLA-I类限制性CTL表
[Abstract]:Group A rotavirus is the leading cause of severe diarrhea in infants and young children around the world. The latest statistics show that about 138 million of patients with rotavirus infection in children under the age of 5 every year in the world, which killed about 454000-705000 cases (82% of deaths occurring in developing countries). At present, there is no specific treatment for rotavirus and drug the safe and effective preventive vaccine, further research on the immune protection mechanism of rotavirus infection is the key and difficult point in current research.
Show that in mice model of rotavirus infection in a large number of studies, TCR +/+CD8+T of alpha and beta cells in anti rotavirus primary infection and reinfection plays an important role. The study found that in the absence of rotavirus antibody, adult mouse rotavirus infection of CD8+ T cells passively protect suckling mice and may be mediated in SCID mice to remove chronic rotavirus infection; cytotoxic T lymphocyte (cytotoxic T lymphocytes CTL (knockout) mice deficient in beta 2-microglobulin mice) and other closed CD8+ T cells of mice cleared rotavirus infection time delayed 1-4 days; B cell defects (J (H) D gene in addition) mice can remove rotavirus primary infection, CD8+ closed after T cells are converted to chronic infection; B cell deficient mice 18 days after primary infection may be mediated by immune protection, almost 6 weeks, 5 months and 8 months can still mediated Part of the immune protection, but closed after CD8+T cell in the original rotation of coronavirus infection in 13 days, 18 days, 6 weeks and 5 months again attack will become chronic rotavirus infection, and closed TCR gamma delta +/+T cells had almost no effect, suggesting that TCR alpha beta +/+CD8+ T cell mediated immune protection re infection of rotavirus. Further study showed that rotavirus structural protein VP6 and VP7 is the main target of.VP6 is the CTL effect of rotavirus antigen, its content accounted for 51% of the total rotavirus protein, the amino acid sequence of the same group of rotavirus VP6 highly conserved (87-99%); VP7 the shell structure protein of rotavirus mainly, accounting for about 30% of the total protein of the virus, at the same time, VP7 can not only cause CTL effect is very strong, and with different serotypes of rotavirus has completely cross reactivity. Although we have simian rotavirus SA11 (G3) and UK (G6 Yuanlun bovine rotavirus The mouse) restricted CTL epitope identification report, but are not used in the study of CD8+T cells of rotavirus infection in the human body. At present, how to position and function of CD8+T cells in human rotavirus infection, is still unknown. So far there is no rotavirus HLA-I restricted CTL table

【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R392

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