ANTIBODY/FC RECEPTOR INTERACTIONS IN AIDS MACAQUE MODELS

描述（由申请人提供）：恒河猴是艾滋病研究和疫苗开发的主要工具。恒河猴基因组序列和恒河猴特异性基因微阵列芯片的出现无疑增加了恒河猴在生物医学研究中的潜力。然而，尽管有这些重大的改进，要完成这个模型的特征描述还有很多工作要做。被动免疫实验以及通过消耗SIV感染的恒河猴B细胞进行的实验的最新发现证实，抗体反应是抵抗SIV引起的感染和疾病的主要保护成分之一。抗体通过将特定抗原与其可变区域结合，然后通过其恒定区域激活效应机制来消除病原体。效应机制的激活是通过恒定区与多种细胞类型上表达的Fc受体的结合而发生的。在非人灵长类动物模型中，各种抗体/Fc受体系统和相关的病原体清除机制在很大程度上仍未被表征。因此，本应用的目的是鉴定恒河猴Fc受体，并定义由这些受体介导的抗体功能特性。为了实现我们的目标，我们将鉴定Fc受体基因，在细胞系中表达这些受体的重组形式，利用重组恒河猴抗体分子研究抗体/受体相互作用，并评估恒河猴IgG和IgA分子触发特异性效应功能的能力。这些研究的结果将为准确评估艾滋病猕猴模型中抗体反应的大小和保护效果提供必要的信息。公共卫生相关性：研制艾滋病疫苗是公共卫生的优先事项。虽然开发这种疫苗需要使用恒河猴模型，但这种模型仍然没有特征。由于已知抗体反应在防止HIV感染中起主要作用，我们建议表征恒河猴体内抗体/Fc受体的相互作用以及由此产生的病原体清除机制。这些研究结果将为优化利用恒河猴模型研制艾滋病疫苗提供必要的信息。

DESCRIPTION (provided by applicant): The rhesus macaque represents a major tool for AIDS research and vaccine development. The recent availability of the rhesus macaque genome sequence and microarray chips of macaque-specific genes has certainly increased the potential of the rhesus macaque in biomedical research. However, despite these major improvements, much needs to be done to complete the characterization of this model. Recent findings from passive immunization experiments as well as from experiments performed by depleting B cells in SIV-infected rhesus macaques confirm that antibody responses represent one of the major protective components against infection and disease caused by SIV. Antibodies eliminate pathogens by binding specific antigens with their variable regions and then by activating effector mechanisms through their constant regions. The activation of effector mechanisms occurs through the binding of the constant regions to Fc receptors expressed on a variety of cell types. The various antibody/Fc receptor systems and related pathogen-clearance mechanisms are still largely uncharacterized in nonhuman primate models. Therefore, the objective of this application is the identification of rhesus macaque Fc receptors and the definition of the antibody functional properties that are mediated by these receptors. To accomplish our objective, we will identify Fc receptor genes, express recombinant forms of these receptors in cell lines for the study of antibody/receptor interactions using recombinant rhesus macaque antibody molecules, and assess the ability of rhesus macaque IgG and IgA molecules to trigger specific effector functions. Results from the proposed studies will provide necessary information to accurately assess magnitude and protective efficacy of antibody responses in AIDS macaque models. PUBLIC HEALTH RELEVANCE: The development of an AIDS vaccine represents a public health priority. Although development of such a vaccine requires the use of rhesus macaque models, such models are still uncharacterized. Because antibody responses are known to play a major role in protecting from HIV infection, we propose to characterize antibody/Fc receptor interactions and resulting pathogen clearance mechanisms in rhesus macaques. Results form these studies will provide needed information for the optimal utilization of rhesus macaque models in developing AIDS vaccines.