T CELL EPITOPES OF THE MALARIA CS PROTEINS

开发一种有效的疟疾疫苗需要鉴定 在保护性免疫中起作用的效应器机制 回应。CD4+辅助性T细胞和细胞毒性T细胞，来源于 子孢子免疫的人类志愿者和黑猩猩识别表位 位于恶性疟原虫和恶性疟原虫的重复区和非重复区。 间日疟原虫环子孢子(CS)蛋白。啮齿动物疟疾模型的研究 这表明，除了辅助细胞功能外，CD4+T细胞还可能 在免疫抵抗中发挥直接作用，要么通过裂解感染的EEF 肝细胞或通过释放淋巴因子来抑制肿瘤的生长 肝细胞内的寄生虫。 为了研究CD4+T细胞介导的针对霍乱病毒的免疫 红外期疟疾，我们将确定是否为天然CS 蛋白质，由可移动的子孢子或受感染的EEF释放 肝细胞，由肝细胞上的第II类处理和呈递，或非 实质细胞，供灵长类CS特异性CD4+细胞识别 体外培养。由于灵长类CD4+效应T细胞的作用无法研究 在活体内，由于伦理和实践的限制，我们将移植人类 肝细胞和灵长类CD4+T细胞进入SCID小鼠。注射后 恶性疟原虫或间日疟原虫的子孢子，我们将确定 移植SCID小鼠提供了一种理想的体内动物模型 针对CS蛋白的灵长类T细胞克隆的效应功能。 为了确定细胞毒的CD4+T细胞是否可以用一种 合成疫苗，我们将用多种抗原肽免疫小鼠 含有恶性疟原虫CS的CD4+CTL表位的系统(MAP) 蛋白。MAPs免疫的小鼠也将被用来确定 该表位还可以诱导辅助性T细胞产生抗 子孢子抗体。为了直接测定CS在体内的作用 特异性的CD4+细胞，我们将使用约氏疟原虫的子孢子免疫的转基因 缺乏CD8+T细胞的小鼠，以确定CD4+T细胞是否可以保护 抗活性子孢子挑战：这些体外和体内研究 将提供有关对红外期的免疫的信息 疟疾寄生虫，希望有助于合理设计一种疟疾 能够诱导细胞毒和/或淋巴因子介导的T细胞的疫苗 效应器机制以及高水平的体液免疫。

The development of an effective malaria vaccine requires the identification of the effector mechanisms which function during a protective immune response. CD4+ helper and cytotoxic T cells, derived from cells of sporozoite-immunized human volunteers and chimpanzees, recognize epitopes located in the repeat and non-repeat regions of the P. falciparum and P. vivax circumsporozoite (CS) protein. Studies in the rodent malaria model suggests that, in addition to their helper cell function, CD4+ T cells may play a direct role in immune resistance, either by lysing EEF infected hepatocytes or by releasing lymphokines that inhibit the growth of the parasite within the liver cell. In order to investigate CD4+ T cell mediated immunity directed against the exoerythrocytic stages of malaria, we will determine whether native CS protein, released by the motile sporozoite or the EEF within infected hepatocytes, is processed and presented by Class II on hepatocytes, or non- parenchymal cells, for recognition by primate CS-specific CD4+ cells in vitro. Since the role of primate CD4+ effector T cells cannot be studied in vivo, due to ethical and practical limitations, we will transplant human hepatocytes and primate CD4+ T cells into SCID mice. Following injection of P. falciparum or P. vivax sporozoites, we will determine whether the engrafted SCID mouse provides a satisfactory in vivo model for the study of effector functions of primate T cell clones specific for the CS protein. In order to determine whether cytotoxic CD4+ T cells can be induced with a synthetic vaccine, we will immunize mice with Multiple Antigen Peptide systems (MAPs) containing the CD4+ CTL epitope of the P. falciparum CS protein. The MAPs immunized mice will also be used to determine whether this epitope can also induce T helper cells for the production of anti- sporozoite antibodies. In order to directly assay the in vivo role of CS specific CD4+ cells, we will use P. yoelii sporozoite-immunized transgenic mice, that lack CD8+ T cells, to determine whether CD4+ T cells can protect against viable sporozoite challenge: These in vitro and in vivo studies will provide information on immunity to exoerythrocytic stages of the malaria parasite and hopefully facilitate the rational design of a malarial vaccine capable of inducing cytotoxic and/or lymphokine-mediated T cell effector mechanisms, as well as high levels of humoral immunity.