Plasmodium vivax promiscuous T-Helper epitopes defined and evaluated as linear peptide chimera immunogens
Plasmodium vivax promiscuous T-Helper epitopes defined and evaluated as linear peptide chimera immunogens
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DOI：
10.1128/iai.70.7.3479-3492.2002
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发表时间：
2002-07-01
影响因子：
3.1
通讯作者：
Moreno, A
中科院分区：
文献类型：
--
作者：
Caro-Aguilar, I;Rodríguez, A;Moreno, A
疟疾疫苗的临床试验证实，需要寄生虫衍生的T细胞表位来激发一致和持久的免疫反应。我们报道了间日疟原虫裂殖子表面蛋白-1(PvMSP-1)中存在的6个T细胞表位的鉴定和功能特性，它们与4个不同的HLA-DRBI*等位基因混杂结合。这些多肽中的每一种都能在感染过间日疟原虫的个体细胞中诱导淋巴增殖反应。此外，与恶性疟原虫免疫优势环子孢子蛋白(CSP)B细胞表位一起合成的含有混合PvMSP-1 T细胞表位的线状多肽嵌合体，在BALB/c小鼠中诱导了高特异性抗体效价、细胞因子产生、持久的免疫应答和免疫球蛋白G亚型类转换。含有等位基因限制性的恶性疟原虫T细胞表位和CSP B细胞表位的线状多肽嵌合体无效。在表现出最高抗肽反应的六个混杂T细胞表位中，有两个也包含B细胞表位。针对这些B细胞表位产生的抗血清在免疫荧光分析中识别间日疟原虫裂殖子。重要的是，针对CSP B细胞表位产生的抗肽抗体抑制了恶性疟原虫子孢子对人肝细胞的侵袭。这些数据和嵌合结构设计的简单性突出了含有寄生虫混杂T细胞表位的多聚体、多阶段和多物种线性多肽嵌合体在疟疾疫苗开发中的潜力。
Clinical trials of malaria vaccines have confirmed that parasite-derived T-cell epitopes are required to elicit consistent and long-lasting immune responses. We report here the identification and functional characterization of six T-cell epitopes that are present in the merozoite surface protein-1 of Plasmodium vivax (PvMSP-1) and bind promiscuously to four different HLA-DRBI* alleles. Each of these peptides induced lymphoproliferative responses in cells from individuals with previous P. vivax infections. Furthermore, linear-peptide chimeras containing the promiscuous PvMSP-1 T-cell epitopes, synthesized in tandem with the Plasmodium falciparum immunodominant circumsporozoite protein (CSP) B-cell epitope, induced high specific antibody titers, cytokine production, long-lasting immune responses, and immunoglobulin G isotype class switching in BALB/c mice. A linear-peptide chimera containing an allele-restricted P. falciparum T-cell epitope with the CSP B-cell epitope was not effective. Two out of the six promiscuous T-cell epitopes exhibiting the highest anti-peptide response also contain B-cell epitopes. Antisera generated against these B-cell epitopes recognize P. vivax merozoites in immunofluoreseence assays. Importantly, the anti-peptide antibodies generated to the CSP B-cell epitope inhibited the invasion of P.falciparum sporozoites into human hepatocytes. These data and the simplicity of design of the chimeric constructs highlight the potential of multimeric, multistage, and multi-species linear-peptide chimeras containing parasite promiscuous T-cell epitopes for malaria vaccine development.