T辅助细胞在疫苗研制中的作用(英文)

The Importance of Helper T-cell Epitope in Vaccine Development

发展感染性疾病疫苗之关键挑战在于利用确定的抗原以刺激产生能引起保护作用的合适的免疫反应。肽类疫苗的运用得到了极大的关注 ,其意义在于 ,已知不同的多表位构成单一结构以诱导出所希望的免疫反应所表现出的灵活性。这一般比利用减毒的活疫苗要安全并且相对而言比制造亚单位疫苗要容易。然而 ,多肽疫苗的发展面临巨大挑战。这一方法在诱导遗传背景复杂的人群免疫反应方面受到限制 ,这与主要组织相溶性复合物 (MHC)多态性有关。因同样的理由 ,肽类免疫应答常因缺乏适当的辅助T淋巴细胞 (HTL)而引导出不充分的细胞毒素T淋巴细胞 (CTL)和抗体反应。另一个运用线性肽链结构的可能缺点是 :为了引导出合适抗体反应 ,表面免疫球蛋白受体簇对于激活静息的B细胞就成为必须因素。由MHC多肽性引起的问题可由运用不加区别的T细胞表位来解决。从麻疹病毒F蛋白 (氨基酸 2 88到 30 2 )中得到的不加区别的T细胞表位和鼠的确定结合在多种MHC分子上的辅助T细胞表位 (V1EB ,aa 191- 2 0 9)已被定性并且被用于能极大激发免疫应答的结构中 ,以克服单一限制型免疫应答的缺陷。合成的 ,非自然PanDR表位 (PADRE)具有退化的结合几种通常HLA DR的能力 ,能以绝对效价和抗体反应质量两种形式来增强激发短肽链的免疫应答。另外 ,?

The major challenge in vaccine development against various disease-causing organisms is to use defined antigen to stimulate appropriate immune responses that lead to resistance. The use of peptide-based vaccine is gaining greater attention as its flexibility in the incorporation of multiple defined and different epitopes into a single construct for eliciting desirable arms of the immune system. It is generally safer than the use of live attenuated vaccine while it is relative ease of manufacture than subunit vaccine. However, development of peptide-based vaccine faces significant challenges. This approach has limited ability to elicit immune responses in a genetically diverse outbred population due to the Major Histocompatibility Complexes (MHC) polymorphism. For the same reason, peptide immunizations often elicit inadequate cytotoxic T lymphocyte (CTL) and antibody (Ab) responses due to the lack of appropriate helper T lymphocyte (HTL) activity. Another possible disadvantage of using linear peptide construct is that, for eliciting appropriate antibody responses, surface immunoglobulin (Ig) receptor clustering is needed in order to activate the resting B cells. Problems caused by MHC polymorphism may be circumvented by the use of promiscuous T-cell epitopes. Promiscuous T-cell epitopes from the measles virus F protein (amino acid 288 to 302) and a murine defined T-helper cell epitope (V1E8, aa 191-209) that bind to multiple MHC molecules have been identified and have been used in highly immunogenic constructs to overcome haplotype-restricted immune responses. Synthetic non-natural Pan DR Epitope (PADRE) which have degenerate binding capacity to several common HLA-DR can enhance immunogenicity of short-peptide immunogen, both in terms of absolute titers and quality of antibody responses. Besides, a number of so called 'promiscuous' T-cell epitopes from Influenza virus hemagglutinin (HA),Plasmodium falciparum pre-erythrocytic stage antigens and mycobacterial proteins have been reported to be universally immunogenic. For promiscuous binding to several isotypic and allotypic forms of MHC class Ⅱ molecules, these peptides should display overlapping MHC-binding motifs or should use anchors that are conserved among ligands and should lack allele-specific anchor residues that would prevent binding with the other class Ⅱ molecules. Understanding the biophysical basis for both the promiscuity and the specificity of peptide recognition by MHC Ⅱ molecules will provide a molecular rationale for strategies to overcome genetic restriction in the context of vaccine design.