REGULATION OF ANTIBODY REPERTOIRE IN AGING

衰老过程中抗体库的调节

• 批准号: 6234331
• 负责人: JAN CERNY
• 金额: $ 23.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234331
• 关键词: B cell receptor; B lymphocyte; CD4 molecule; CD44 molecule; SCID mouse; aging; animal old age; antibody formation; antibody specificity; cell age; cellular immunity; gene mutation; germ cells; haptens; helper T lymphocyte; humoral immunity; immunization; immunogenetics; immunoglobulin genes; immunologic memory; immunomodulators; immunoregulation; juvenile animal; phosphorylcholine

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.

老年动物和人类的抗体反应可能会改变 大小和/或抗体分子的结构。 长期 该提议的目的是阐明那些人的机制 免疫学变化及其对老年人能力的影响 使用小鼠抗体的实验模型来抵抗感染 针对肺炎链球菌菌株R36A（PN）的反应。 PN抗体反应， 针对免疫主导的细菌表位， 磷酸胆碱（PC），可保护小鼠免受致命感染 肺炎球。 由年轻小鼠产生的PC抗体分子（2-6 莫。年龄）由V（d）J遗传段的单个组合编码 指定为T15基因。 令人惊讶的是，由老化产生的抗体（> 20 mo old）老鼠可能很健壮，但似乎是由不同的编码 种系Ig基因。 第一个建议的目的是确定多少 不同的V基因家族编码PC特异性的H和L链 由老年小鼠产生的杂交瘤AB。 选定的VH（V-D-J）区域将 与相比 来自年轻mab的类似基因。 遗传转移对 老化的PC抗体的特异性和对抗脑癌活性将是 在主动和被动保护实验中确定。 随后的 目的是基于与年龄相关的抗体库移动的机制。 一个 纯化淋巴细胞的收养转移将用于确定是否是否 老化的前B细胞单独或单独或 该移位是否受老化的T细胞影响。 能力 老化的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抗原的反应 与年轻捐助者和老年捐助者的T细胞子集重组。 提议 研究将确定（a）老化的CD4+细胞是否无法驱动 生发中心的形成以及躯体多样化 抗体库，（b）年龄小鼠的PC响应的大小为 由遗传组成o宿主通过与t相关的机制确定 细胞。