MECHANISMS OF NONSTERILIZING IMMUNITY IN MALARIA

在世界许多地区，疟疾发病率和死亡率继续不受控制。 随着开发有效疫苗的努力的增加，很明显，关于介导抑制受感染宿主中寄生虫血症的免疫机制知之甚少。 针对疟疾的细胞介导的免疫（CMI）和抗体介导的免疫（AMI）都依赖于CD 4 + α T细胞的活化。 该提案的目的是研究不同T细胞激活信号对在缺乏所研究的特定分子的基因敲除（KO）小鼠的新模型中发展针对血液期夏氏疟原虫疟疾的保护性免疫的功能。 待检测的激活信号是通过IL-2受体激活CD 4 +T辅助细胞的细胞因子、促炎细胞因子（IFN-γ、IL-12和TNF α）、共刺激分子（CD 40 L和CD 28）和T细胞受体（TCR α和TCR γ）。 待评估的免疫参数是寄生虫血症、感染结果、淋巴细胞亚群扩增、活化标志物表达、细胞因子和巨噬细胞活化标志物产生、细胞因子和巨噬细胞活化产生。 夏氏疟原虫寄生虫血症被细胞介导的或抗体免疫机制抑制，从而提供了评价KO小鼠中激活信号的功能的机会，该KO小鼠限于通过CMI或AMI抑制寄生虫血症。 P. Chabaudi感染KO小鼠提供了一个很好的模型，用于研究这些信号，因为它允许解剖的控制信号，调节AMI和CMI的参与，这两个参与保护性免疫对这两个鼠疟原虫和人恶性疟原虫。 这项拟议研究的结果将提供预测感染结果的T细胞和巨噬细胞活化概况，并揭示免疫的细胞和分子机制，可作为免疫预防和/或免疫治疗的靶点。

malaria morbidity and mortality continue to go unchecked in many arts of the world. As efforts mount to develop an effective vaccine, it is readily apparent that little is know regarding the immune mechanisms mediating suppression of parasitemia in the infected host. Both cell- mediated immunity (CMI) and antibody-mediated immunity (AMI) against malaria are dependent upon the activation of CD4+alphabeta T cells. The goal of this proposal is to examine the function of different T cell activating signals on the development of protective immunity against blood-stage P chabaudi malaria in the novel model of knockout (KO) mice lacking genes for the particular molecule being studied. The activating signals to be examined are cytokines activating CD4+T helper cells through the IL-2 receptor, proinflammator cytokines (IFN-gamma, IL-12 and TNFalpha), co-stimulatory molecules (CD40L and CD28) and T cell receptors (TCRalphabeta and TCRgammazeta). The parameters of immunity to be assessed are parasitemia, outcome of infection, expansion of lymphocyte subsets, expression of activation markers, production of cytokines and macrophage activation markers, production of cytokines and macrophage activation. P. Chabaudi parasitemia is suppressed by cell- mediated or antibody mechanisms of immunity thereby providing the opportunity to evaluate the function of activating signals in KO mice limited to suppressing parasitemia by either CMI or AMI. P. Chabaudi infection of KO mice provides an excellent model for studying these signals because it allows dissecting of the controlling signals that regulate the participation of AMI and CMI, both of which participate in protective immunity against both this murine malarial parasite and human P. Falciparum. The results of this proposed research will provide profiles of T cell and macrophage activation predictive of the out come of infection and reveal the cellular and molecular mechanisms of immunity that may serve as targets for immunoprophylaxis and/or immunotherapy.