MIMETICS OF CAPSULAR EPITOPES OF NEISSERIA MENINGITIDIS

描述（改编自申请人的摘要）的长期目标 这项研究旨在增加我们对免疫学特性的理解， 一种细菌多糖的分子模拟物，也是一种自身抗原。 模拟物可以作为抗原，与B细胞上的抗体受体结合，并引发 对标称抗原的血清抗体应答。然而， 关于抗原模拟物的特性， 免疫原性对抗体反应的质量也知之甚少 关于赋予针对病原体的保护。Neisseria 脑膜炎B群（NmB）多糖是研究 这些问题。NmB是脑膜炎和败血症的主要原因。机制 的保护是明确定义的（血清抗体），并存在可靠的检测方法， 抗体与多糖抗原结合的功能性测量 抗细菌的抗体，并在婴儿大鼠模型中进行被动保护， 菌血症开发NmB疫苗的努力受到了贫困的阻碍 与宿主发生交叉反应的多糖胶囊的免疫原性 聚唾液酸PI的实验室制备了一组鼠单克隆抗体， 与NmB上的荚膜多糖表位反应的抗体（Mab）， 与宿主聚唾液酸不同。这些单克隆抗体具有杀菌作用， 动物模型中的被动保护。私家侦探的假设是 由这些单克隆抗体鉴定的抗原将能够引起保护性免疫应答， 抗荚膜抗体反应，特异性的病原体，避免 自身抗体的风险。此外，最好的模拟物将是那些 采用相对稳定的构象。为了寻找这种模拟物，PI 提出筛选展示独立折叠肽的噬菌体文库， 或在免疫球蛋白支架内寻找受约束的蛋白质模拟物 （单链可变（ScFv）抗独特型）。模仿者会 研究它们引发抗囊抗体应答的能力。的 IG同种型、针对细菌的抗体功能活性和免疫球蛋白 响应于模拟物的可变区基因使用，将与 由标称抗原引发的免疫反应一个核心问题是， 用与包封的NmB特异性反应的Mab鉴定的模拟物 菌株，但不与宿主聚唾液酸，将引发保护性抗体 无自身抗体活性的反应。其他问题将是， 对模拟物的抗体应答库是相似的或不同的 比由标称多糖引起的更大，以及如果有的话， 抗体库可能没有保护作用。总而言之，这些数据将 提供关于模拟抗原性质的重要信息， 与标称多糖不同的化学结构 抗原的这些结果还可以鉴定出新的候选分子， 一种预防NmB疾病的未来疫苗。

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.