EFFECTOR AND MEMORY ANTIMALARIA CD8+ CELL RESPONSES

效应器和记忆抗疟 CD8 细胞反应

• 批准号: 6497122
• 负责人: FIDEL P ZAVALA
• 金额: $ 39.94万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497122
• 关键词: Plasmodium; SCID mouse; T cell receptor; antigen antibody reaction; cellular immunity; enzyme linked immunosorbent assay; female; flow cytometry; genetically modified animals; immunologic memory; immunoregulation; immunotherapy; leukocyte activation /transformation; major histocompatibility complex; malaria; malaria vaccines; nonhuman therapy evaluation; polymerase chain reaction; suppressor T lymphocyte; vaccinia virus; vector vaccine

Recent vaccination attempts using different immunogens such as viral vectors, DNA or synthetic constructs expressing pre-erythrocytic malaria antigens or their T cell epitopes, have provided important new information regarding the protective role of these T cells. It was shown that mice immunized with different immunogens, including selected viral vectors, expressing the same plasmodial sequence, induce malaria-specific CD8+ T cells which strongly inhibit liver stage development, conferring sterile immunity to a significant proportion of the immunized mic. These studies and others have raised a number of important questions related to the induction of effector and memory CD8+ T cell responses which need to be answered in order to further advance the design and development of an effective malaria vaccine. We propose to undertake studies aimed at characterizing some basic aspects of the in vivo CD8+ T cell responses against the liver stages of P. yoelii. We propose to identify the parameters which closely reflect the in vivo anti-parasite activity of effector and memory CD8+ T cells and characterize the optimal conditions to establish efficient effector and memory CD8+ T cell responses. We also propose to study the immuno-regulatory mechanisms controlling the in vivo induction and maintenance of effector and memory CD8+ T cell responses. Using transgenic mice expressing a T cell receptor specific for a CD8+ T cell epitope of the P. yoelii CS protein , recently generated in my laboratory, we will study the molecular and functional properties characterizing the differentiation of CD8+ T cells from naive to effector and memory cells. Other transgenic mice expressing a pertinent class I MHC only in hepatocytes, also recently generated in my laboratory, will be used to evaluate the role of hepatocytes in the induction/activation of effector and memory CD8+ T cells directed against P. yoelii liver stages. Finally we propose studies aimed at enhancing the magnitude and efficacy of effector and memory CD8+ T cell responses by immunization with double recombinant vaccinia viruses expressing the P. yoelii CS protein and cytokines known to exert important immunomodulatory effects on T cell responses.

最近使用不同免疫原子（例如病毒载体，DNA或合成构建体）表达前肉眼疟疾抗原或其T细胞表位的疫苗接种尝试提供了有关这些T细胞保护作用的重要新信息。 结果表明，用不同的免疫原子免疫的小鼠，包括选定的病毒载体，表达相同的质量序列，诱导疟疾特异性的CD8+ T细胞，这些CD8+ T细胞极大地抑制肝脏阶段的发育，从而赋予无菌免疫，从而相当比例的免疫MIC。 这些研究以及其他研究提出了许多重要的问题，与诱导效应子和记忆CD8+ T细胞反应有关，这些反应需要回答，以进一步推进有效的疟疾疫苗的设计和开发。我们建议进行旨在表征体内CD8+ T细胞反应的一些基本方面的研究，以针对P. yoelii的肝脏阶段进行表征。 我们建议确定效应子和记忆CD8+ T细胞体内抗寄生虫活性的参数，并表征最佳条件，以建立有效的效应子和内存CD8+ T细胞响应。 我们还建议研究控制效应子和记忆CD8+ T细胞反应的体内诱导和维持的免疫调节机制。 我们使用表达对叶叶氏疟原虫CS蛋白的CD8+ T细胞表位的转基因小鼠，最近在我的实验室中产生，我们将研究表征CD8+ T细胞从天真到效应子和记忆细胞区分的分子和功能特性。 仅在我的实验室中也产生的肝细胞中表达相关I类MHC的其他转基因小鼠将用于评估肝细胞在效应子和记忆CD8+ T细胞诱导/激活中针对P. yoelii肝阶段的作用。 最后，我们提出的研究旨在通过用双重重组疫苗病毒免疫来增强效应子和记忆CD8+ T细胞反应的大小和功效，表达P. yoelii CS蛋白和已知的细胞因子和已知的细胞因子对TT细胞反应施加重要的未经许可效应。