AIDS Vaccine Strategy Using IgG Transfer Pathway

使用 IgG 转移途径的艾滋病疫苗策略

• 批准号: 7458667
• 负责人: XIAOPING ZHU
• 金额: $ 18.39万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458667
• 关键词: AIDS Vaccines; Adult; Animals; Antibodies; Antigens; Apical; Cells; Chimeric Proteins; Chlamydia; Class; Clinic; Cytomegalovirus; Data; Epithelial; Epithelial Cells; Fc Immunoglobulins; Female; Fetus; Foundations; Genital system; Genus Mycobacterium; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Immune response; Immunity; Immunization; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulins; In Vitro; Infection; Influenza; Intestines; Invaded; Knockout Mice; Life; Lower respiratory tract structure; Lymphoid Tissue; Mediating; Mucosal Immune Responses; Mucosal Immunity; Mus; Neonatal; Newborn Infant; Pathway interactions; Patients; Placenta; Proteins; Rodent; Route; Simplexvirus; Subunit Vaccines; Surface; Testing; Thinking; Tissues; Vaccine Antigen; Vaccines; Vaccinia virus; Viral Antigens; Virus; Virus Diseases; base; concept; design; genital secretion; monolayer; mucosa-associated lymphoid tissue; neonatal Fc receptor; novel; pathogen; prevent; respiratory; transmission process; virus envelope

DESCRIPTION (provided by applicant): Transmission of Human Immunodeficiency Virus (HIV) occurs primarily via the mucosal routes, emphasizing HIV-1 vaccines must need to engender mucosal immune responses. However, mucosal immunization has been limited by the ability to deliver intact vaccine antigens across the mucosal barrier for induction of effective mucosal immunity. The long-term goal of this proposal is to determine whether the IgG transcellular pathway represents a novel delivery path for a subunit vaccine against infections of HIV and AIDS-related opportunistic pathogens. The goal of the project derives from the recent proof of concept that the neonatal Fc receptor (FcRn) mediates the bi-directional transport of IgG across polarized epithelial cells. FcRn was initially considered to transport maternal IgG to a fetus through the placenta or to newborns via the intestine. However, FcRn is expressed in a variety of tissues and cells in adult humans and animals; IgG is a predominant isotype of immunoglobulins in the lower respiratory and genital tract. Based on these evidences, we will test the hypothesis that using IgG transport pathway, FcRn can deliver HIV-1 antigen fused to an IgG-Fc across the mucosal barrier to the underlying mucosa-associated lymphoid tissue. The consequences of such transport could induce local immunity able to neutralize the virus at their port of entry and systemic immunity able to prevent systemic spread of the infection. HIV envelope glycoprotein gp120 will be used to probe immune responses to such immunization and to define protective immune responses. The specific aim of this proposal is to determine the ability of FcRn to deliver gp120-Fc antigen across the genital or the respiratory mucosal barrier to engender protective immunity against mucosallv-inoculated virus challenge. Data generated herein will provide valuable information not only for design of a HIV vaccine, but also for general vaccine strategy targeting AIDS-associated opportunistic pathogens or other pathogens, such as cytomegalovirus, herpes simplex virus, mycobacterium, chlamydia, influenza, etc., that infect at or invade across mucosal surfaces.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）的传播主要通过粘膜途径发生，强调HIV-1疫苗必须产生粘膜免疫反应。然而，粘膜免疫一直受到通过粘膜屏障递送完整的疫苗抗原以诱导有效粘膜免疫的能力的限制。这项提议的长期目标是确定IgG跨细胞途径是否代表了一种新的亚单位疫苗的递送途径，以对抗HIV和艾滋病相关的机会性病原体感染。该项目的目标源于最近的概念证明，即新生儿Fc受体（FcRn）介导IgG在极化上皮细胞间的双向转运。FcRn最初被认为是通过胎盘或通过肠道将母体IgG转运给胎儿。然而，FcRn在成人和动物的多种组织和细胞中表达；IgG是下呼吸道和生殖道中主要的免疫球蛋白同型。基于这些证据，我们将验证假设，通过IgG转运途径，FcRn可以将HIV-1抗原融合到IgG- fc，通过粘膜屏障传递到粘膜相关淋巴组织。这种运输的后果可能诱发能够在其入境口岸中和病毒的局部免疫和能够防止感染的全身传播的全身免疫。HIV包膜糖蛋白gp120将用于探测对这种免疫的免疫反应，并确定保护性免疫反应。本提案的具体目的是确定FcRn通过生殖器或呼吸道粘膜屏障递送gp120-Fc抗原的能力，以产生针对粘膜接种病毒攻击的保护性免疫。本文产生的数据不仅将为HIV疫苗的设计提供有价值的信息，而且还将为针对艾滋病相关的机会性病原体或其他病原体（如巨细胞病毒、单纯疱疹病毒、分枝杆菌、衣原体、流感等）感染或侵入粘膜表面的一般疫苗策略提供有价值的信息。