TARGETED IMMUNOGEN DELIVERY TO MURINE DENDRITIC CELLS

完全阻断宿主感染的唯一免疫机制是 通过特异性抗体识别入侵病原体。因此，一种理想 疫苗是一种诱导肝脏长期产生这种中和作用的疫苗。 抗体。这项提议旨在制定战略，以增强 并延长对中和表位的体液免疫反应 通过靶向递送外来抗原感染病原体 小鼠补体受体2型(CR2；CD21)。外国与中国的互动 小鼠CR2抗原对原发体液免疫反应至关重要 对T依赖和T非依赖的抗原，以及S的诱导 对免疫记忆的影响。这种免疫调节作用被认为是 C3补体抗原配体与CR2-CD19的相互作用 B淋巴细胞上的膜复合体和/或通过定位和持久性 在滤泡树突状细胞上表达的这些抗原在运送到CR2时的表达 细胞。这些观察表明，将免疫原定向递送到 CR2将增强记忆反应中的初级记忆反应 接种疫苗。这一假说将通过对流感的研究来探索。 这种病毒之所以被选中，有几个原因。流感是一种 重要的人类病原体，特别是在婴儿和老年人中 目前的疫苗只有部分有效。抗体 病毒表面糖蛋白血凝素(HA)的特异性是 流感感染的初级防御和中和表位 关于HA的定义已经很好了。此外，还有病毒株可供选择 已经适应了小鼠的致病性，以及小鼠的免疫 对流感的反应有很好的特点。实验性的 该方法将涉及用C3-HA融合蛋白或 携带C3的流感病毒应针对两个淋巴细胞 滤泡树突状细胞(FDC)。体内保护作用的研究进展 与流感的挑战将与传统的流感进行比较 疫苗以及本文件中描述的其他新型流感疫苗 求婚。还将确定免疫调节是否 C3-HA免疫对流感的应答是通过CR2介导的 通过对RAG-2的类似研究在淋巴细胞和/或FDC上表达 用正常胚胎或正常胚胎重组的缺陷小鼠 干细胞在两个淋巴细胞上都表达补体受体 和FDC或与已提供补体的胚胎干细胞 通过基因打靶而缺乏受体，以至于它们只表达CR2 在FDC上。

The only immunologic mechanism that completely blocks host infection is recognition of the invading pathogen by specific antibody. Thus, an ideal vaccine is one that induces long-liver production of such neutralizing antibodies. This proposal is designed to develop strategies that enhance and prolong the humoral immune response to neutralizing epitopes on infectious pathogens through targeted delivery of foreign antigens to murine complement receptor type 2 (CR2; CD21). Interaction of foreign antigen with murine CR2 is critical for the primary humoral immune response to both T-dependent and T-independent antigens, as well s for the induction of immunologic memory. This immunomodulatory effect is thought to result from interaction of antigen bearing C3 complement ligands with the CR2-CD19 membrane complex on B lymphocytes and/or via localization and persistence of such antigens upon delivery to CR2 expressed on follicular dendritic cells. These observations suggest that targeted delivery of immunogens to CR2 will enhance both the primary as eell as the anamnestic response during vaccination. This hypothesis will be explored through studies of influenza virus which has been chosen for several reasons. influenza is a significant human pathogen, particularly among infants and the elderly population, and current vaccines are only partially effective. Antibodies specific for the viral surface glycoprotein hemaggglutinin (HA) are the primary defense against influenza infection, and the neutralizing epitopes on HA have been well defined. Furthermore, viral strains are available that have been adapted for pathogenicity in mice, and the murine immune response to influenza has been well characterized. The experimental approach will involve immunization of mice with C3-HA fusion proteins or C3-bearing influenza virus which should be targeted to both lymphocytes and follicular dendritic cells (FDC). The protective effect during in vivo challenge with influenza will be compared with a traditional influenza vaccine as well as with other novel influenza vaccines described in this proposal. It will also be determined whether modulation of the immune response to influenza by immunization with C3-HA is mediated via CR2 expressed on lymphocytes and/or on FDC through similar studies in RAG-2 deficient mice that have been reconstituted with either normal embryonic stem cells such that they express complement receptors on both lymphocytes and FDC or with embryonic stem cells that have been rendered complement receptor deficient through gene targeting, such that they express CR2 only on FDC.