T-INDEPENDENT IGA INDUCTION AND HIV-1 VACCINATION

描述：（改编自申请人的摘要）伊加同种型的抗体 被认为是粘膜上B细胞源性免疫的主要介质 网站.在直肠和生殖器粘膜中诱导抗原特异性伊加可以 在防止性传播病原体方面特别重要， 例如人类免疫缺陷病毒（HIV-1）。多年来，调查 主要集中在T依赖的B细胞激活途径，导致 诱导抗原特异性伊加。相比之下， 以探索伊加诱导的T非依赖性途径。已经 几十年来，一些胸腺非依赖性抗原可以诱导伊加 应答最近建立了一种T细胞缺陷型小鼠品系（C57 BL， α β/γ δ T细胞受体敲除，-/-小鼠）为我们提供了一个 简化模型，以研究体内T-非依赖性B细胞反应， 没有任何T细胞。当特异性微生物多糖抗原， α（1-6）葡聚糖注射到这些小鼠中，大量的 引发抗原特异性B细胞，主要是伊加同种型。的 脾中抗原特异性IgA分泌细胞的数量约为 高于正常小鼠或注射了结构上不同的 多糖B1355 S。这些发现清楚地表明， 在活体动物中的伊加诱导的T-非依赖性（TI）途径，并确定了一个 多糖抗原，α（1-6）葡聚糖，作为一种有效的刺激剂， 分泌IgA的B细胞。在这个提案中，我们计划调查：1）α可以吗？ (1-6)葡聚糖用作载体和/或佐剂以引发伊加应答， 其他抗原决定簇？2)含有α（1-6）葡聚糖的缀合物 促进免疫球蛋白伊加反应的gp 120糖蛋白的HIV-1？3)有哪些 这些抗原的最佳给药途径， 粘膜部位的伊加？由于其独特的T-独立特性， 这类疫苗不仅对正常人有效， 在T细胞系统严重受损的艾滋病患者中， 预防艾滋病毒的治疗性疫苗。该原则也可适用于 研制预防艾滋病中经常发生的机会性感染的疫苗 患者和其他T细胞缺乏综合征。

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.