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: 7230380
• 负责人: XIAOPING ZHU
• 金额: $ 21.45万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230380
• 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，粘膜免疫受到跨粘膜屏障递送完整疫苗抗原以诱导有效粘膜免疫的能力的限制。该提案的长期目标是确定 IgG 跨细胞途径是否代表了针对 HIV 和 AIDS 相关机会性病原体感染的亚单位疫苗的新递送途径。该项目的目标源自最近的概念证明，即新生儿 Fc 受体 (FcRn) 介导 IgG 跨极化上皮细胞的双向运输。 FcRn 最初被认为可通过胎盘将母体 IgG 转运至胎儿或通过肠道转运至新生儿。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免疫球蛋白的主要同种型。基于这些证据，我们将检验以下假设：利用 IgG 转运途径，FcRn 可以将与 IgG-Fc 融合的 HIV-1 抗原穿过粘膜屏障递送至下方的粘膜相关淋巴组织。这种运输的后果可能会诱导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系统性传播的全身免疫。 HIV 包膜糖蛋白 gp120 将用于探测对此类免疫的免疫反应并定义保护性免疫反应。该提案的具体目的是确定 FcRn 跨生殖器或呼吸道粘膜屏障递送 gp120-Fc 抗原以产生针对粘膜接种病毒攻击的保护性免疫的能力。本文生成的数据不仅为HIV疫苗的设计提供有价值的信息，而且为针对艾滋病相关机会性病原体或其他病原体（例如巨细胞病毒、单纯疱疹病毒、分枝杆菌、衣原体、流感等）的一般疫苗策略提供有价值的信息，这些病原体感染或侵入粘膜表面。