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的病原体。 因此，一个理想 疫苗是一种诱导长肝产生这种中和 抗体的 该提案旨在制定战略， 并延长对中和表位的体液免疫应答， 通过靶向递送外源抗原， 鼠补体受体2型（CR2; CD 21）。 外国的互动 具有鼠CR2的抗原对于初次体液免疫应答是关键的 T依赖性和T非依赖性抗原，以及用于诱导 免疫记忆。 这种免疫调节作用被认为是导致 来自带有抗原的C3补体配体与CR2-CD 19的相互作用 B淋巴细胞上的膜复合物和/或通过定位和持久性 这些抗原在递送至在滤泡树突状细胞上表达的CR2后 细胞 这些观察结果表明，靶向递送免疫原， CR2将增强初级和记忆反应， 预防针 这一假设将通过对流感的研究来探讨 选择这种病毒有几个原因。 流感是一 重要的人类病原体，特别是婴儿和老年人 目前的疫苗只是部分有效。 抗体 对病毒表面糖蛋白血凝素（HA）具有特异性的是 抗流感感染的初级防御，以及中和表位 对HA的定义已经明确。 此外，病毒株是可用的 已经适应了小鼠的致病性， 对流感的反应已得到很好的描述。 实验 方法将涉及用C3-HA融合蛋白免疫小鼠，或 携带C3的流感病毒，应靶向两种淋巴细胞 和滤泡树突细胞（FDC）。 在体内期间的保护作用 流感病毒的挑战将与传统流感病毒进行比较 疫苗以及本文所述的其他新型流感疫苗 提议 还将确定免疫调节是否 通过用C3-HA免疫对流感的应答经由CR2介导 通过RAG-2中的类似研究，在淋巴细胞和/或FDC上表达 用正常的胚胎干细胞或 干细胞，使得它们在两个淋巴细胞上表达补体受体， 和FDC或胚胎干细胞， 通过基因靶向使受体缺陷，使得它们仅表达CR2 关于FDC

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.