REPERTOIRE OF BACTERIAL ANTIBODY IN AGING

描述：（改编自申请人摘要）抗体应答 老年动物和人类的变化可能在幅度和/或 抗体分子的结构。 本项目的长期目标 是阐明这些免疫学变化的机制，以及它们的 对老年人抵抗感染能力的影响，使用 小鼠抗S.肺炎菌菌株 R36a（Pn）。 Pn-抗体反应，这是针对 免疫显性细菌表位，磷酸胆碱（PC），保护 小鼠对抗致命的肺炎球菌感染。 PC抗体分子 由年轻/成年小鼠（2-6个月）产生。 旧的）由单个 V（D）J基因片段的组合命名为T15基因。 令人惊讶的是，由老化（大于20个月）的小鼠产生的抗体。 旧） 老鼠可能很健壮，但它似乎是由不同的编码， 生殖系IG基因。 第一个提议的目标是确定 不同的V基因家族编码Pc特异性的H和L链， 杂交瘤Ab由老年小鼠产生。 选择的VH（V-D-J）区将 测序以评估体细胞突变的程度，与 年轻老鼠的相似基因。 基因转移对 老化PC抗体的特异性和抗肺炎球菌活性将 在主动和被动保护实验中确定。 后续 目的是年龄相关的抗体库转变的机制。 一个 纯化淋巴细胞的过继转移将用于确定 老化的前B细胞是否发育成不同的PC反应性克隆， 或者这种转变是否受到老化T细胞的影响。 的 衰老T细胞调节衰老T细胞数量和多样性的能力 将在体外和体内研究对PC抗原的抗体应答。 用来自年轻和老年供体的T细胞亚群重建的无胸腺小鼠。 拟议的研究将确定（a）老化的CD 4细胞是否 来驱动生发中心的形成， 抗体库的多样化，和（B）PC的大小 老年小鼠的免疫应答取决于宿主的生殖细胞构成 通过与T细胞相关的机制。

DESCRIPTION: (Adapted from applicant's abstract) The antibody responses of aged animals and humans may change in the magnitude and/or in the structure of antibody molecules. The long-term objective of this project is to elucidate the mechanisms of those immunological changes, and their effects on the ability of aged individuals to resist infections, using an experimental model of mouse antibody response against S. pneumoniae strain R36a (Pn). The Pn-antibody response, which is directed against the immunodominant bacterial epitope, phosphorylcholine (PC), protects the mice against lethal infection with pneumococci. The PC antibody molecules produced by young/adult mice (2-6 mo. old) are encoded by a single combination of V (D) J genetic segments designated as T15 genes. Surprisingly, the antibody produced by aged (greater than 20 mo. old) mice may be quite robust, but it appears to be encoded by different germline Ig genes. The first proposed aim is to determine as to how many different V gene families encode the H and L chains of Pc-specific hybridomas Ab generated from aged mice. Selected VH (V-D-J) regions will be sequenced to assess the extent of somatic mutations, in comparison with similar genes from young mice. The effects of genetic shift on the specificity and anti-pneumococcal activity of aged PC-antibody will be determined in both active and passive protection experiment. Subsequent aims are on the mechanisms of age-related antibody repertoire shift. An adoptive transfer of purified lymphocytes will be used to determine whether the aged pre-B cells develop into different PC-reactive clones, alone or whether the shift is influenced by the aged T cells. The competence of aged T cells to regulate the magnitude and the diversity of antibody response to PC antigens will be studied both in vitro and in athymic mice reconstituted with T cell subsets from young and aged donors. The proposed studies will determine whether (a) the aged CD4- cells fail to drive the formation of germinal centers as well as the somatic diversification of the antibody repertoire, and (b) the magnitude of PC response in aged mice is determined by the germline make-up of the host via a mechanism related to T cells.