CAJ | 학술논문

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288到302)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 191-209)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Pan DR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,一些所谓的从流感病毒血凝素(HA)来的"不加区别的"T细胞表位,恶性疟疟原虫红细胞前期抗原和分枝杆菌蛋白被报道能激发广泛的免疫应答.为了不加区别地结合于几种同型和同种异型的MHCⅡ类分子,这些肽类应显示出部重叠MHC结合形式或应利用保存于配体中的固定位点和应缺失等位基因特异性固定残基,以防止结合于其它Ⅱ类分子.了解MHCⅡ类分子对肽链的不加区别及特异性识别的生物物理学基础将为在疫苗设计中突破遗传限制的策略提供分子水平的依据. 髮展感染性疾病疫苗之關鍵挑戰在于利用確定的抗原以刺激產生能引起保護作用的閤適的免疫反應.肽類疫苗的運用得到瞭極大的關註,其意義在于, 已知不同的多錶位構成單一結構以誘導齣所希望的免疫反應所錶現齣的靈活性.這一般比利用減毒的活疫苗要安全併且相對而言比製造亞單位疫苗要容易.然而,多肽疫苗的髮展麵臨巨大挑戰.這一方法在誘導遺傳揹景複雜的人群免疫反應方麵受到限製,這與主要組織相溶性複閤物(MHC)多態性有關.因同樣的理由,肽類免疫應答常因缺乏適噹的輔助T淋巴細胞 (HTL)而引導齣不充分的細胞毒素T淋巴細胞(CTL)和抗體反應.另一箇運用線性肽鏈結構的可能缺點是:為瞭引導齣閤適抗體反應,錶麵免疫毬蛋白受體簇對于激活靜息的B細胞就成為必鬚因素.由MHC多肽性引起的問題可由運用不加區彆的T細胞錶位來解決.從痳疹病毒F 蛋白(氨基痠288到302)中得到的不加區彆的T細胞錶位和鼠的確定結閤在多種MHC分子上的輔助T細胞錶位(V1EB,aa 191-209)已被定性併且被用于能極大激髮免疫應答的結構中,以剋服單一限製型免疫應答的缺陷.閤成的,非自然Pan DR錶位(PADRE)具有退化的結閤幾種通常HLA-DR的能力,能以絕對效價和抗體反應質量兩種形式來增彊激髮短肽鏈的免疫應答 .另外,一些所謂的從流感病毒血凝素(HA)來的"不加區彆的"T細胞錶位,噁性瘧瘧原蟲紅細胞前期抗原和分枝桿菌蛋白被報道能激髮廣汎的免疫應答.為瞭不加區彆地結閤于幾種同型和同種異型的MHCⅡ類分子,這些肽類應顯示齣部重疊MHC結閤形式或應利用保存于配體中的固定位點和應缺失等位基因特異性固定殘基,以防止結閤于其它Ⅱ類分子.瞭解MHCⅡ類分子對肽鏈的不加區彆及特異性識彆的生物物理學基礎將為在疫苗設計中突破遺傳限製的策略提供分子水平的依據.
발전감염성질병역묘지관건도전재우이용학정적항원이자격산생능인기보호작용적합괄적면역반응.태류역묘적운용득도료겁대적관주,기의의재우, 이지불동적다표위구성단일결구이유도출소희망적면역반응소표현출적령활성.저일반비이용감독적활역묘요안전병차상대이언비제조아단위역묘요용역.연이,다태역묘적발전면림거대도전.저일방법재유도유전배경복잡적인군면역반응방면수도한제,저여주요조직상용성복합물(MHC)다태성유관.인동양적이유,태류면역응답상인결핍괄당적보조T림파세포 (HTL)이인도출불충분적세포독소T림파세포(CTL)화항체반응.령일개운용선성태련결구적가능결점시:위료인도출합괄항체반응,표면면역구단백수체족대우격활정식적B세포취성위필수인소.유MHC다태성인기적문제가유운용불가구별적T세포표위래해결.종마진병독F 단백(안기산288도302)중득도적불가구별적T세포표위화서적학정결합재다충MHC분자상적보조T세포표위(V1EB,aa 191-209)이피정성병차피용우능겁대격발면역응답적결구중,이극복단일한제형면역응답적결함.합성적,비자연Pan DR표위(PADRE)구유퇴화적결합궤충통상HLA-DR적능력,능이절대효개화항체반응질량량충형식래증강격발단태련적면역응답 .령외,일사소위적종류감병독혈응소(HA)래적"불가구별적"T세포표위,악성학학원충홍세포전기항원화분지간균단백피보도능격발엄범적면역응답.위료불가구별지결합우궤충동형화동충이형적MHCⅡ류분자,저사태류응현시출부중첩MHC결합형식혹응이용보존우배체중적고정위점화응결실등위기인특이성고정잔기,이방지결합우기타Ⅱ류분자.료해MHCⅡ류분자대태련적불가구별급특이성식별적생물물이학기출장위재역묘설계중돌파유전한제적책략제공분자수평적의거.
The major challenge in vaccine development a gainst 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 asits flexibility in the incorporation of multiple defined and different epitopes into a single construct for eliciting d esirable arms of the immune system. It is generally safer than the use of live a ttenuated 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 dive rse outbred population due to the Major Histocompatibility Complexes (MHC) polym orphism. For the same reason, peptide immunizations often elicit inadequate cyto toxic T lymphocyte (CTL) and antibody (Ab) responses due to the lack of appropri ate helper Tlymphocyte (HTL) activity. Another possible disadvantage of using linear peptide construct is that, for eliciting appropriate antibody responses, s urface immunoglobulin (Ig) receptor clustering is needed in order to activate th e 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 mea sles virus F protein (amino acid [aa] 288 to 302) and a murine defined T-helper cell epitope (V1E8, aa 191-209) that bind to multiple MHC molecules have bee n identified and have been used in highly immunogenic constructs to overcome hap lotype-restricted immune responses. Synthetic non-natural Pan DR Epitope (PADR E) 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 reporte d to be universally immunogenic. For promiscuous binding to several isotypic and allotypic forms of MHC class Ⅱ molecules, these peptides should display overla pping MHC-binding motifs or should use anchors that are conserved among ligands and should lack allele-specific anchor residues that would prevent binding wit h 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.