REGULATION OF ANTIBODY REPERTOIRE IN AGING

老年动物和人类的抗体反应可能会在 抗体分子的大小和/或结构。长期的 这项建议的目的是阐明这些机制 免疫学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 对肺炎链球菌R36a(Pn)的反应。PN抗体反应， 它是针对免疫优势细菌表位的， 磷胆碱(PC)，保护小鼠免受致死性感染 肺炎球菌。幼年/成年小鼠产生的PC抗体分子(2-6 莫。年龄)由V(D)J遗传片段的单个组合编码 命名为T15基因。令人惊讶的是，老年人(&gt；20)产生的抗体 小鼠可能相当健壮，但它似乎是由不同的 生殖系免疫球蛋白基因。第一个提议的目标是确定有多少人 不同的V基因家族编码Pc特异的H链和L链 老年小鼠产生的杂交瘤抗体。选定的VH(V-D-J)区域将 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。基因转移对人类健康的影响 老年PC抗体的特异性和抗肺炎球菌活性将被 在主动和被动保护实验中均已确定。后续 目的是研究与年龄相关的抗体谱变化的机制。一个 将通过过继转移纯化的淋巴细胞来确定 老化的前B细胞发育成不同的PC反应克隆，单独或 这种转变是否受到衰老T细胞的影响。……的能力 老化T细胞调节抗体的大小和多样性 对PC抗原的反应将在体外和胸腺小鼠中进行研究。 用年轻和老年捐赠者的T细胞亚群重组。建议数 研究将确定：(A)衰老的CD4+细胞是否未能推动 生发中心的形成和体细胞的多样化 抗体库，以及(B)老龄小鼠的PC反应量为 由寄主的遗传构成通过与T相关的机制决定的 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.