Characteristics and protective efficacy of human antibodies against M. tuberculosis

摘要 活动性肺结核(TB)，一种由分枝杆菌引起的可传播的无节制呼吸道感染 结核病是一个全球性的公共卫生问题，也是全球十大死因之一。更多 迫切需要有效的预防结核病的疫苗。目前可用的卡米特芽孢杆菌- 盖林(BCG)疫苗已经使用了近一个世纪，但对结核病的保护不足。一个 结核病疫苗领域的主要障碍是对免疫成分的全面了解有限 参与了预防结核病的工作。目前，结核病疫苗的开发重点是诱导或促进细胞- 介导性免疫，但越来越多的证据表明，抗体也在预防 结核病。为了更好地了解可以在人类身上诱导的特定保护性抗体反应 通过疫苗接种，对人多克隆抗体和单抗进行了详细的鉴定和功能研究 到潜在的保护性表位是必需的。针对囊膜和其他表面多糖的抗体是 防止几种微生物病原体，包括那些位于细胞内的病原体，如结核分枝杆菌。人类 结核分枝杆菌荚膜多糖的抗体水平不仅变化很大，而且也很大。 它们与多糖中的寡糖基序的结合专一性不同。我们出版的和 初步数据表明，这种保护作用是由于免疫球蛋白对特定寡糖基序的反应。基于 这些新的数据，我们的主要假设是：1)人类对特定的荚膜多糖的抗体 对结核分枝杆菌具有保护作用；2)这些抗体的保护作用源于对特定寡糖的反应。 多糖体中的基序。我们的具体目标是：1.制备和鉴定人类多克隆和 单抗对结核分枝杆菌表面糖链的影响；2.检测单抗对巨噬细胞的影响 目的：研究结核分枝杆菌表面特异性人源抗体的体内保护作用。 我们的首要目标是确定结核分枝杆菌表面碳水化合物的寡糖表位 与保护相关，尽管我们一些最成功的疫苗是基于诱导抗体 在胶囊多糖领域，已经开始转向寡糖结合疫苗，这此外 以最相关的表位为目标，与 市面上最常见的糖结合疫苗纯化多糖的异种制剂。这个 所获得的知识可以为开发疫苗和基于抗体的免疫疗法的新战略提供依据 抗结核病。

Abstract Active tuberculosis (TB), a transmissible uncontrolled respiratory infection caused by Mycobacterium tuberculosis (Mtb), is a global public health problem and one of the top 10 causes of death worldwide. More effective vaccines for the protection against TB are urgently needed. The currently available Bacillus Calmette- Guerin (BCG) vaccine has been in use for almost a century but provides insufficient protection against TB. A major obstacle in the TB vaccine field is the limited understanding of the full breadth of the immune components involved in the protection against TB. Currently, TB vaccine development is focused on eliciting or boosting cell- mediated immunity, but increasing evidence suggests that antibodies also have a role in the protection against TB. To gain a better understanding of specific protective antibody responses that could be induced in humans by vaccination, detailed characterization and functional studies of human polyclonal and monoclonal Abs (mAbs) to potentially protective epitopes are required. Antibodies to capsular and other surface polysaccharides are protective against a several microbial pathogens, including those with intracellular location such as Mtb. Human antibody levels to Mtb capsular polysaccharides are not only greatly variable, they are also tremendously heterogeneous in their binding specificity to oligosaccharide motifs within the polysaccharide. Our published and preliminary data suggest that protection is due to IgG reactivity to specific oligosaccharide motifs. Based on these novel data, our overarching hypotheses are: 1) Human antibodies to specific capsular polysaccharides are protective against Mtb; and 2) protection by these antibodies arises from reactivity to specific oligosaccharide motifs within the polysaccharide. Our specific aims are: 1. To generate and characterize human polyclonal and mAbs to Mtb surface glycans; 2. To determine the effects of Mtb surface-specific human Abs on macrophage functions; and 3. To establish the protective efficacy of Mtb surface-specific human Abs in vivo. Our overarching goal is to determine the oligosaccharide epitopes of Mtb surface carbohydrates that are most relevant for protection Although some of our most successful vaccines are based on inducing antibodies to capsular polysaccharides, the field has started to move to oligosaccharide-conjugate vaccines, which, in addition to targeting the most relevant epitopes, have the advantage of greater product consistency compared to the heterogeneous preparations of purified polysaccharides of most marketed glycoconjugate vaccines. The knowledge gained could inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.