MIMETICS OF CAPSULAR EPITOPES OF NEISSERIA MENINGITIDIS

描述(改编自申请人的摘要) 本研究旨在加深我们对猪传染性支气管炎的免疫学特性的了解。 细菌多糖的分子模拟，也是自身抗原。 模拟物可以作为抗原，与B细胞上的抗体受体结合，并诱导 血清对标称抗原的抗体反应。然而，人们对此知之甚少。 关于抗原模拟物的特性，这些特性有助于他们的 免疫原性。抗体反应的质量也不是很清楚。 关于授予对病原体的保护。奈瑟氏菌 脑膜炎B组(NMB)多糖是一个很好的研究模型 这些问题。NMB是脑膜炎和败血症的主要原因。这一机制 保护的范围是明确的(血清抗体)，并且存在可靠的检测方法 功能性多糖类抗原结合抗体的测定 针对细菌的抗体，以及对幼鼠模型的被动保护 菌血症。开发NMB疫苗的努力因贫困而受阻 与宿主发生交叉反应的多糖胶囊的免疫原性 聚唾液酸。PI的实验室已经准备了一组小鼠的单抗 与NMB上的衣壳多糖表位反应的抗体(MAb) 与寄主聚唾液酸不同。这些单抗具有杀菌作用 动物模型中的被动保护。少年派的假设是模仿 由这些单抗识别的抗原将能够诱导保护性 针对病原体的抗囊膜抗体反应，避免 自身抗体的风险。此外，最好的模仿将是那些 采用相对稳定的构象。为了寻找这样的模仿，PI 建议筛选独立展示折叠多肽的噬菌体文库， 或者在免疫球蛋白支架中寻找受限制的蛋白质模拟物 (单链可变(ScFv)抗独特型)。模仿将会是 研究它们诱导抗囊性抗体反应的能力。这个 免疫球蛋白亚型、对细菌的抗体功能活性和免疫球蛋白 可变区基因的使用对模拟的响应，将与 这是由标称抗原引起的。一个中心问题将是一个 用能与被包裹的NMB特异反应的单抗鉴定的模拟物 菌株，但不与宿主聚唾液酸一起，会引起保护性抗体 无自身抗体活性的反应。其他问题将是 对模拟物的抗体反应谱系相似或不同 以及，如果有的话，有什么作用？ 抗体库可能有保护作用。综合来看，这些数据将 提供有关模拟抗原特性的重要信息 与标称多糖不同的化学结构 抗原。结果还可能确定新的候选分子，包括在 未来用于预防NMB疾病的疫苗。

Description (Adapted from the applicant's abstract) The long-term objective of this study is to increase our understanding of the immunologic properties of molecular mimetics of a bacterial polysaccharide that also is an autoantigen. Mimetics can act as antigens, bind to antibody receptors on B cells, and elicit serum antibody responses to the nominal antigen. Yet, little is understood about the properties of antigenic mimetics that contribute to their immunogenicity. Nor is much known about the quality of the antibody response with respect to conferring protection against a pathogen. Neisseria meningitidis group B (NmB) polysaccharide is an excellent model to investigate these questions. NmB is a major cause of meningitis and sepsis. The mechanism of protection is well defined (serum antibody), and reliable assays exist for measurement of antibody binding to the polysaccharide antigen, functional antibody against the bacteria, and passive protection in an infant rat model of bacteremia. Efforts to develop a NmB vaccine have been hampered by poor immunogenicity of the polysaccharide capsule, which cross-reacts with host polysialic acid. The PI's laboratory has prepared a panel of murine monoclonal antibodies (Mabs) that react with capsular polysaccharide epitopes on NmB that are distinct from host polysialic acid. These Mabs are bactericidal and confer passive protection in animal models. The PI's hypothesis is that mimetic antigens identified by these Mabs will be able to elicit protective anti-capsular antibody responses that are specific for the pathogen, avoiding the risk of autoantibody. Further, that the best mimetics will be those that adopt relatively stable conformations. To search for such mimetics, the PI proposes to screen phage libraries displaying independently folding peptides, or search for constrained protein mimetics within immunoglobulin scaffolds (single chain variable (ScFv) anti-idiotypes). The mimetics will be investigated for their ability to elicit anticapsular antibody responses. The Ig isotype, antibody functional activity to the bacteria, and immunoglobulin variable region gene usage in response to the mimetics, will be compared to that elicited by the nominal antigen. A central question will be whether a mimetic identified with a Mab that reacts specifically with encapsulated NmB strains, but not with host polysialic acid, will elicit protective antibody responses without autoantibody activity. Additional questions will be whether the repertoire of the antibody response to the mimetic is similar or different than that elicited by the nominal polysaccharide, and what effect, if any, the antibody repertoire may have on protection. Taken together, the data will provide important information on the properties of mimetic antigens with chemical structures that are distinct from that of the nominal polysaccharide antigen. The results also may identify new candidate molecules for inclusion in a future vaccine for prevention of NmB disease.