Early Plasma Cells as a Source of Anthrax-Neutralizing Antibodies

炭疽杆菌是一种致病性很强的细菌，因为它的芽胞形态稳定，可以抵抗治疗。 使用抗生素，它的抗吞噬胶囊，以及它产生的强大毒素。因此，它一直被研究为 生物战剂已有约60年的历史，是一种极其有效的恐怖主义武器。我们有 最近开发了一种新的策略，在免疫后快速生产完全的人类单抗 并建议使用这项技术来开发针对炭疽病的治疗性抗体。这些抗体是 重组来源于早期抗体分泌免疫球蛋白可变区基因的表达 免疫后7天出现大量、短暂的细胞爆裂。这项技术代表了 从人类生产单抗方面的实质性进展，并提供了一个机会 迅速发展抗体疗法。我们现在已经使用这一战略生产了有限数量的 来自炭疽疫苗接受者的抗体。在与我们的U19团队的合作中，我们使用了血清学 研究确定几个关键的多肽表位，有效中和炭疽毒素活性。中环 该技术组件的目标是分离针对这些表位的单抗。这些 抗体作为评估保护性免疫的研究和诊断试剂将是有价值的，并可能 最终被开发用于安全的被动免疫或用于治疗炭疽感染。此外, 对单抗反应性的分析可以识别非显性的保护性抗体特异性。 在多克隆反应中，或只出现针对非肽的结构表位。尽管一种疫苗 预防炭疽病的存在和使用有限，主要用于军事人员的疫苗接种，其有效性为 充其量只能是“好的”。它需要多次和持续的助推才能提供保护，我们的U19小组已经 确定只有一半的免疫者的血清可以中和炭疽毒性。这样就有了第二个目标 对这一成分的研究是为了表征诱导长期B细胞免疫(记忆)以获得洞察 为什么疫苗在诱导保护性免疫方面相对无效。

The bacterium Bacillus anthracis is highly pathogenic because of its stable spore form that resists treatment with antibiotics, its antiphagocytic capsule, and its production of potent toxins. Thus it has been studied as agent of biological warfare for some 60 years and is an extremely effective terrorist weapon. We have recently developed a novel strategy to rapidly produce fully human monoclonal antibodies after immunization and propose to use this technique to develop therapeutic antibodies against anthrax. These antibodies are derived recombinantly from expression of the immunoglobulin variable region genes of early antibodysecreting cells that arise in a massive, transient burst 7 days after immunization. This technology represents a substantial advance in monoclonal antibody production from humans and provides an opportunity to rapidly develop antibody therapies. We have now used this strategy to produce a limited number of antibodies from recipients of the anthrax vaccine. In collaboration with our U19 team we used serological studies to identify several key peptide epitopes that effectively neutralize anthrax toxin activity. The central goal of this Technology Component is to isolate the monoclonal antibodies that target these epitopes. These antibodies will be valuable as research and diagnostic reagents to assess protective immunity, and could ultimately be developed for safe passive immunization or for treatment of anthrax infection. In addition, analyses of monoclonal antibody reactivity may identify protective antibody specificities that are not dominant in the polyclonal response, or that only arise against non-peptide, structural epitopes. Although a vaccine against anthrax exists and is in limited use, primarily for vaccination of military personnel, its effectiveness is at best only "good". It requires multiple and continued boosts to provide protection, and our U19 group has determined that serum from only half of those immunized can neutralize anthrax toxicity. Thus a second goal of this component is to characterize the induction of long-term B cell immunity (memory) to gain insight into why the vaccine is relatively ineffective in inducing protective immunity.