利用人HLA Ⅰ类分子表型特异性细胞观察恶性疟原虫CTL表位的内源递呈及其与Ⅰ类分子的交连反应
摘要
杀伤性T淋巴细胞(CTL)是红细胞前期恶性疟原虫免疫防护的关键环节。有效的CTL反应可以阻断疟原虫的生活周期，是目前极受关视的疟疾疫苗设计方案。HLA Ⅰ类分子的多态性限制了旨在刺激产生CTL的免疫治疗工作对人群的保护范围，使抗疟疫苗的研究明显复杂化。CTL多表位重组疫苗的构建是目前解决HLA Ⅰ类分子多态性一个较好的途径。当前恶性疟CTL疫苗研究所面临的另一个问题是缺乏合适的动物模型。开展有关的体外研究，对疫苗潜在的免疫原性进行体外预测，不仅是必然的，而且是可能的。
近年来的研究发现一些HLA Ⅰ类分子结合肽的锚定位点的氨基酸残基具有重叠性，这些锚定残基被称为HLA分子结合肽基序(Motif)，具有相同肽基序一类HLA Ⅰ类分子组成一个HLA Ⅰ类分子结合超亚型(Supertype)，现有的几乎所有的HLA-A和-B分子都被包括在九个这样的超亚型中。每个结合超亚型对应的共同的肽基序则称为共用肽段(supermotif)。含有相应共用肽段的肽常可与同一结合超亚型的不同HLA Ⅰ发生交连反应。HLA结合亚型和共用肽段的发现，为克服MHC多态性的CTL疫苗设计提供了一个崭新的设想，即通过寻找能与多个HLA Ⅰ类分子结合的表位，代替上述常见多表位疫苗的研究。从而避免了后者繁琐复杂的工作，提高了工作效率，是CTL疫苗研究的新方向。
本实验所选用两个恶性疟抗原CTL表位TR和SH，均来自非洲株系，其中TR来自thrombspondin相关的尚未命名蛋白(TRAP)，为HLA-2.1限制；SH来源于子孢子肝细胞结合抗原1(SHEBA)，己证实与HLA-B51有高亲和力。上述两个恶性疟CTL表位分别含有HLA-A2和HLA-B7超亚型的共用肽段。
将对应于以上表位的DNA序列设计成微型基因tr和sh。并将其分别克隆到真核细胞表达载体pcDNA3.1／Hygro(+)，构建两个重组质粒pcDNA3.1／tr和
CD8+ cytotoxic T lymphocytes (CTL) play a critical role in eradicating Plasmodium falciparum at the pre-erythrocyte stage of the parasite infection. Many interests have been transferred to CTL vaccine design aimed at blocking the pathogen life cycle. The efforts to develop a Plasmodium falciparum CTL vaccine has been complicated by the polymorphism of MHC class I molecules. It had been suggested that to construct a multiple CTL epitope vaccine would be helpful to solve the problem. Owing to the lack of suitable and affordable animal model for Plasmodium falciparm researches at present, a preliminary in vitro assay to predicate recombinant vaccine immunogenicity would be helpful and feasible.
Recent researches indicated that some HLA class I molecules peptides showed overlapping peptide ligand anchor residues, the anchor residues is known as the peptide-binding motif. The HLA molecules that are characterized by same or similar peptide-binding motifs were defined as a supertype. It appears that all known HLA class I A and B alleles might be classified in one of nine supertypes. The peptide-binding motif shared by one supertypes HLA class I alleles was defined as supermotif. It had been demonstrated that the existence of broadly crossreactive peptides in a supertype HLA alleles. The definition of supermotif and supertype, has important implication for Plasomodium vaccine design. That is, instead of developing, a single peptide entity for each of HLA alleles, to attempt the identification of epitopes capable of binding multiple HLA type and avoid the complexities linked to development of a vaccine comprising a large number of epitopes.
近年来的研究发现一些HLA Ⅰ类分子结合肽的锚定位点的氨基酸残基具有重叠性，这些锚定残基被称为HLA分子结合肽基序(Motif)，具有相同肽基序一类HLA Ⅰ类分子组成一个HLA Ⅰ类分子结合超亚型(Supertype)，现有的几乎所有的HLA-A和-B分子都被包括在九个这样的超亚型中。每个结合超亚型对应的共同的肽基序则称为共用肽段(supermotif)。含有相应共用肽段的肽常可与同一结合超亚型的不同HLA Ⅰ发生交连反应。HLA结合亚型和共用肽段的发现，为克服MHC多态性的CTL疫苗设计提供了一个崭新的设想，即通过寻找能与多个HLA Ⅰ类分子结合的表位，代替上述常见多表位疫苗的研究。从而避免了后者繁琐复杂的工作，提高了工作效率，是CTL疫苗研究的新方向。
本实验所选用两个恶性疟抗原CTL表位TR和SH，均来自非洲株系，其中TR来自thrombspondin相关的尚未命名蛋白(TRAP)，为HLA-2.1限制；SH来源于子孢子肝细胞结合抗原1(SHEBA)，己证实与HLA-B51有高亲和力。上述两个恶性疟CTL表位分别含有HLA-A2和HLA-B7超亚型的共用肽段。
将对应于以上表位的DNA序列设计成微型基因tr和sh。并将其分别克隆到真核细胞表达载体pcDNA3.1／Hygro(+)，构建两个重组质粒pcDNA3.1／tr和
CD8+ cytotoxic T lymphocytes (CTL) play a critical role in eradicating Plasmodium falciparum at the pre-erythrocyte stage of the parasite infection. Many interests have been transferred to CTL vaccine design aimed at blocking the pathogen life cycle. The efforts to develop a Plasmodium falciparum CTL vaccine has been complicated by the polymorphism of MHC class I molecules. It had been suggested that to construct a multiple CTL epitope vaccine would be helpful to solve the problem. Owing to the lack of suitable and affordable animal model for Plasmodium falciparm researches at present, a preliminary in vitro assay to predicate recombinant vaccine immunogenicity would be helpful and feasible.
Recent researches indicated that some HLA class I molecules peptides showed overlapping peptide ligand anchor residues, the anchor residues is known as the peptide-binding motif. The HLA molecules that are characterized by same or similar peptide-binding motifs were defined as a supertype. It appears that all known HLA class I A and B alleles might be classified in one of nine supertypes. The peptide-binding motif shared by one supertypes HLA class I alleles was defined as supermotif. It had been demonstrated that the existence of broadly crossreactive peptides in a supertype HLA alleles. The definition of supermotif and supertype, has important implication for Plasomodium vaccine design. That is, instead of developing, a single peptide entity for each of HLA alleles, to attempt the identification of epitopes capable of binding multiple HLA type and avoid the complexities linked to development of a vaccine comprising a large number of epitopes.
引文
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