DESIGN AND IMMUNE MECHANISMS OF P FALCIPARUM CS VACCINE

能够诱导免疫的有效疟疾疫苗的设计 主要是抗体或细胞介导的反应，或理想的是 两者的结合，需要对所有效应器的全面了解， 保护机制。恶性疟原虫和鼠疟的研究 寄生虫已经表明，针对重复和非重复的抗体 这些环子孢子蛋白的区域可以减少或消除 通过阻断寄生虫/宿主细胞的相互作用来提高寄生虫的感染性。在 此外，由CD 4+和CD 8+介导的细胞介导的免疫应答 细胞毒性T淋巴细胞和/或淋巴因子，可以破坏随后的 寄生虫在细胞内发育的阶段 肝细胞为了更好地了解分子基础和独特的 每个效应器的免疫机制的作用，并制定最佳的 能够诱导这些多重免疫应答的免疫原，我们 提议： 1.诱导保护性细胞毒性T细胞反应，以及中和 用重组活载体免疫的抗子孢子抗体 含有约氏疟原虫和约氏疟原虫的CS蛋白的确定序列。 恶性疟原虫。 2.定义II类药物的特异性、动力学和作用机制 限制性CD 4+细胞毒性和辅助性T细胞，来源于子孢子- 免疫人、灵长类动物和小鼠宿主并测定免疫原性 和含有这些表位的MAP构建体的抗原性 CD 4 + T细胞。 3.开发针对保守非重复序列的单克隆抗体 伯氏疟原虫和恶性疟原虫的CS蛋白的功能区域 作为寄生虫/宿主细胞受体相互作用的配体， 这些单克隆抗体是否能抑制子孢子的感染性。

The design of an effective malaria vaccine capable of inducing an immune response that is primarily antibody or cell mediated, or ideally a combination of both, requires a through knowledge of all the effector mechanisms of protection. Studies on P. falciparum and on rodent malaria parasites have shown that antibody against repeat, as well as non-repeat regions of these circumsporozoite proteins can decrease or abolish parasite infectivity by blocking parasite/host cell interactions. In addition, cell mediated immune responses, mediated by CD4+ and CD8+ cytotoxic T lymphocytes and/or lymphokines, can destroy the subsequent stages of intracellular development of the parasite within the hepatocyte. In order to better understand the molecular basis and unique role of each effector mechanisms of immunity, and to develop optimal immunogens capable of inducing these multiple immune responses, we propose to: 1. Induce a protective cytotoxic T cell response, as well as neutralizing antisporozoite antibodies by immunization with recombinant live vectors containing defined sequences of the CS protein of P. yoelii and P. falciparum. 2. Define the specificity, kinetics and mechanism of action of class II restricted CD4+ cytotoxic and helper T cell, derived from sporozoite- immunized human, primate and murine hosts and assay the immunogenicity and antigenicity of MAPs constructs containing epitopes defined by these CD4+ T cells. 3. Develop monoclonal antibodies specific for conserved non-repeat regions of the CS proteins of P. berghei and P. falciparum which function as ligands in parasite/host cell receptor interactions and determine whether these monoclonals can inhibit sporozoite infectivity.