T-INDEPENDENT IGA INDUCTION AND HIV-1 VACCINATION

描述：(改编自申请人摘要)免疫球蛋白A同型抗体 被认为是粘膜中B细胞衍生免疫的主要介体 网站。直肠和生殖器粘膜中抗原特异性IgA的诱导可以 在防止性传播病原体方面尤为重要， 例如人类免疫缺陷病毒(HIV-1)。多年来，调查 主要关注T依赖的B细胞激活途径，这会导致 诱导抗原特异性免疫球蛋白A。相比之下，几乎没有做出什么努力 探索T非依赖性的免疫球蛋白A诱导途径。一直以来 几十年来人们就知道一些胸腺非依赖性抗原可以诱导IgA 回应。最近建立了一株T细胞缺陷小鼠(C57BL， Alphaβ/Gamma Delta T细胞受体敲除，-/-小鼠)为我们提供了 研究T非依赖性B细胞体内反应的简化模型 任何T细胞的缺失。当一种特定的微生物多糖抗原， α(1-6)葡聚糖，注射到这些小鼠体内，大量 抗原特异性B细胞被激发出来，主要是IgA同型。这个 脾中抗原特异性IgA分泌细胞的数量约为30倍 高于正常小鼠或注射了结构明显不同的 多糖，B1355S。这些发现清楚地说明了 在活体动物中诱导IgA的T非依赖性(TI)途径，并鉴定了一种 多糖抗原，α(1-6)葡聚糖，作为一种有效的刺激因子 分泌IgA的B细胞。在这项提案中，我们计划调查：1)阿尔法 (1-6)葡聚糖作为载体和/或佐剂诱导IgA应答 其他抗原决定簇？2)α(1-6)-葡聚糖结合物 促进IgA对HIV-1 gp120糖蛋白的反应？3)什么是 获得抗原特异性的最佳给药途径(S) 粘膜部位的免疫球蛋白？具有独特的T-独立特征，这是 一类疫苗不仅对正常人有效，而且对 在T细胞系统严重受损的艾滋病患者中， 针对艾滋病毒的治疗性疫苗。这一原则也可适用于 开发针对艾滋病频繁发生的机会性感染的疫苗 患者和其他T细胞缺陷综合征。

DESCRIPTION: (Adapted from Applicant's Abstract) Antibodies of the IgA isotype are believed to be the major mediator of the B cell derived immunity at mucosal sites. Induction of the antigen-specific IgA in rectal and genital mucosa can be particularly important in protection against sexually transmitted pathogens, such as the human immunodeficiency virus (HIV-1). For years, investigations focused primarily on the T-dependent route of B-cell activation that leads to induction of antigen specific IgA. In contrast, little effort has been performed to explore the T-independent route of IgA induction. It has been known for decades that some thymus-independent antigens can induce IgA responses. Recent establishment of a strain of T-cell deficient mice (C57BL, alpha beta/ gamma delta T-cell receptor knock-out, -/- mice) provided us a simplified model to investigate the T-independent B-cell responses in vivo in the absence of any T cell. When a specific microbial polysaccharide antigen, alpha (1-6) dextran, was injected into these mice, a large number of antigen-specific B cells, predominately of the IgA isotype, were elicited. The number of antigen specific IgA-secreting cells in spleen is about 30 fold higher than those in normal mice or mice injected with a structurally distinct polysaccharide, B1355S. These findings illustrated clearly the presence of a T-independent (TI) route of IgA induction in living animals and identified a polysaccharide antigen, alpha (1-6) dextran, as a potent stimulator of IgA-secreting B cells. In this proposal, we plan to investigate: 1) Can alpha (1-6) dextran serve as a carrier and/or adjuvant to elicit IgA responses to other antigenic determinants? 2) Can alpha (1-6) dextran-containing conjugates facilitate IgA responses to the gp120 glycoprotein of HIV-1? 3) What are the optimal route(s) of administration of these antigens to elicit antigen specific IgA at mucosal sites? With the unique T-independent characteristics, this category of vaccines can be effective not only in normal individuals but also in AIDS patients whose T-cell systems were severely impaired, serving as therapeutic vaccinations against HIV. The principle may also be applied to develop vaccines against opportunistic infections occurring frequently in AIDS patients and in other T-cell deficient syndromes.