Mapping of immune responses following wild-type and mutant ABeta42 plasmid or peptide vaccination in different mouse haplotypes and HLA Class II transgenic mice
Mapping of immune responses following wild-type and mutant ABeta42 plasmid or peptide vaccination in different mouse haplotypes and HLA Class II transgenic mice
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DOI：
10.1016/j.vaccine.2005.08.036
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发表时间：
2006-05-22
期刊：
影响因子：
5.5
通讯作者：
Ugen, Kenneth E.
中科院分区：
文献类型：
--
作者：
Kutzler, Michele A.;Cao, Chuanhai;Ugen, Kenneth E.
尽管最近针对阿尔茨海默病（AD）的A β 42肽疫苗的临床试验由于不良事件而停止，但这种方法的明显临床效用强调了进一步提高疫苗安全性以及了解并发症的潜在免疫学基础的必要性。在这项研究中，我们研究了在不同免疫单倍型的小鼠以及HLA II类转基因小鼠中，通过用编码野生型和A β 42的佛兰芒和荷兰突变（即β淀粉样肽跨越氨基酸1-42）的肽或DNA免疫引起的体液和细胞免疫应答。佛兰芒和荷兰突变与受影响个体的脑血管疾病有关。这些数据允许确定潜在的免疫反应，这些免疫反应可能介导β淀粉样蛋白突变形式观察到的病理学，并导致更安全的疫苗制剂的产生。在肽或质粒免疫后，在ELISA测定中测量针对不同A β 42肽的抗体应答，同时通过干扰素γ ELISPOT和淋巴细胞增殖测定分析T细胞表位。B细胞作图研究表明，来自接种任何A β 42肽的所有单倍型小鼠的血清与A β 42的前10个氨基酸特异性反应，其中A β 42突变体引发更高的免疫应答。ELISPOT分析，其访问细胞免疫应答，表明小鼠表达依赖于不同免疫单倍型的I类表位的差异。这些结果可能对未来基于A β 42的阿尔茨海默病疫苗的设计具有影响。(c)2005爱思唯尔有限公司保留所有权利。
Although the recent clinical trial of the ABeta42 peptide vaccine against Alzheimer's Disease (AD) has been halted due to adverse events, the apparent clinical utility of this approach underscores the need to further improve the safety of the vaccine, as well as to understand the potential immunological basis for complications. In this study, we examine both humoral and cellular immune responses elicited by immunization with peptide or DNA encoding wild-type and the Flemish and Dutch mutations of ABeta42 (i.e. the beta amyloid peptide spanning amino acids 1-42) in mice of different immune haplotypes as well as HLA Class II transgenic mice. The Flemish and Dutch mutations have been associated with cerebrovascular hemorrhages in affected individuals. These data allow determination of potential immunological responses that could mediate pathology observed with mutant forms of amyloid beta, as well as lead to the generation of safer vaccine preparations. Following peptide or plasmid immunization, antibody responses were measured against the different ABeta42 peptides in an ELISA assay, while T cell epitopes were analyzed through interferon gamma ELISPOT and lymphocyte proliferation assays. B cell mapping studies indicated that sera from all of the haplotype mice vaccinated with any of the ABeta42 peptides reacted specifically to the first 10 amino acids of ABeta42 with the ABeta42 mutants eliciting higher immune responses. ELISPOT analysis, which accessed cellular immune responses indicated that mice expressed differences in Class I epitopes dependent on the different immune haplotypes. These results may have implications for the design of future ABeta42 based vaccines against Alzheimer's Disease. (c) 2005 Elsevier Ltd. All rights reserved.