REGULATION OF ANTIBODY REPERTOIRE IN AGING

老年动物和人类的抗体反应可能会在 量和/或抗体分子的结构。 长期 本建议的目的是阐明这些机制， 免疫变化及其对老年人能力的影响 为了抵抗感染，使用小鼠抗体的实验模型， 针对S.肺炎R36 a（Pn）菌株。 Pn-抗体反应， 其针对免疫显性细菌表位， 磷酸胆碱（PC），保护小鼠免受致命的感染， 肺炎球菌。 由年轻/成年小鼠产生的PC抗体分子（2-6 密苏里州年龄）由V（D）J基因片段的单一组合编码 命名为T15基因。 令人惊讶的是，由老年人（>20岁）产生的抗体 老鼠可能很强壮，但它似乎是由不同的基因编码的。 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 进行测序，以评估体细胞突变的程度，与 与年轻的Mab相似的基因。 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是否 老化的前B细胞单独或单独发育成不同的PC反应性克隆 这种转变是否受到老化的T细胞的影响。 的权限 衰老T细胞调节抗体的大小和多样性 将在体外和胸腺小鼠中研究对PC抗原的应答 用来自年轻和老年供体的T细胞亚群重建。 拟议 研究将确定（a）老化的CD 4+细胞是否无法驱动 形成的germinal中心，以及体细胞的多样化， 抗体库，和（B）老年小鼠中PC应答的幅度是 通过与T相关的机制由宿主的遗传组成决定 细胞

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 proposal 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. pneumonia 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. age) are encoded by a single combination of V (D) J genetic segments designated as T15 genes. Surprisingly, the antibody produced by aged (>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 asses the extent of somatic mutations, in comparison with similar genes from young Mab. The effects of genetic shift on the specificity and antipneumococcal activity of aged PC-antibody will be determined in both active and passive protection experiments. 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 thymic 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 age mice is determined by the genetic make-up o the host via a mechanism related to T cells.