MECHANISMS OF NONSTERILIZING IMMUNITY IN MALARIA

疟疾的非灭菌免疫机制

• 批准号: 6372958
• 负责人: WILLIAM Paul WEIDANZ
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372958
• 关键词: CD4 molecule; Plasmodium falciparum; SCID mouse; T cell receptor; T lymphocyte; athymic mouse; cellular immunity; cytokine; cytokine receptors; flow cytometry; genetically modified animals; helper T lymphocyte; host organism interaction; immunity; immunofluorescence technique; immunosuppression; interleukin 2; leukocyte activation /transformation; malaria; microorganism immunology; monoclonal antibody; neutralizing antibody; polymerase chain reaction; protozoal antigen

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.

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不断增加，很明显，对于受感染宿主体内介导寄生虫病抑制的免疫机制知之甚少。针对疟疾的细胞介导免疫（CMI）和抗体介导免疫（AMI）都依赖于CD4+ α T细胞的激活。本研究的目的是在缺乏特定分子基因的敲除（KO）小鼠模型中，研究不同T细胞激活信号在抗血期P型夏博迪疟疾保护性免疫发展中的功能。要检测的激活信号是通过IL-2受体、促炎细胞因子（ifn - γ、IL-12和TNFalpha）、共刺激分子（CD40L和CD28）和T细胞受体（tcrα β和TCRgammazeta）激活CD4+T辅助细胞的细胞因子。待评估的免疫参数包括寄生虫血症、感染结局、淋巴细胞亚群扩增、激活标记物表达、细胞因子和巨噬细胞激活标记物产生、细胞因子产生和巨噬细胞激活。P. Chabaudi寄生虫病受到细胞介导或抗体免疫机制的抑制，从而为评估仅受CMI或AMI抑制寄生虫病的KO小鼠激活信号的功能提供了机会。Chabaudi感染的KO小鼠为研究这些信号提供了一个很好的模型，因为它允许解剖调节AMI和CMI参与的控制信号，两者都参与对这种小鼠疟原虫和人类恶性疟原虫的保护性免疫。这项研究的结果将提供T细胞和巨噬细胞活化的概况，预测感染的结果，揭示免疫的细胞和分子机制，可能作为免疫预防和/或免疫治疗的靶点。