REPERTOIRE OF BACTERIAL ANTIBODY IN AGING

描述：(改编自申请人的摘要)抗体反应 老年动物和人类的数量可能会在大小和/或 抗体分子结构。这个项目的长期目标是 是为了阐明这些免疫变化的机制，以及它们的 对老年人抵抗感染能力的影响，使用 肺炎链球菌小鼠抗体应答实验模型的建立 R36a(PN)。PN抗体反应，它是针对 免疫优势细菌表位，磷胆碱(PC)，保护 使小鼠免受肺炎球菌的致死性感染。PC抗体分子 由幼年/成年小鼠产生(2-6mo.旧的)由单个 指定为T15基因的V(D)J基因片段的组合。 令人惊讶的是，年龄(大于20mo)产生的抗体。旧的) 老鼠可能相当健壮，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 与幼鼠相似的基因。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是 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 衰老的前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衰老T细胞的影响。这个 衰老T细胞调节T细胞数量和多样性的能力 对PC抗原的抗体反应将在体外和在 由年轻和老年捐赠者的T细胞亚群重组的无瘤小鼠。 拟议的研究将确定：(A)老化的cd4细胞是否会衰竭。 以推动生发中心和体细胞的形成 抗体谱系的多样化，以及(B)PC的大小 衰老小鼠的反应由宿主的生殖系构成决定 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.