IMMUNOMODULATION BY EXOGENOUS STREPTOCOCCAL ANTIBODY

外源链球菌抗体的免疫调节

• 批准号: 6516634
• 负责人: L. Jeannine Brady
• 金额: $ 30.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516634
• 关键词: Streptococcus mutans; Streptococcus vaccine; human tissue; humoral immunity; immunization; immunoconjugates; immunomodulators; laboratory mouse; monoclonal antibody; mucosal immunity; nonhuman therapy evaluation; vaccine development

DESCRIPTION: (adapted from the Investigator's abstract): Systemic immunization with antigen coupled to monoclonal antibody (mAb) has been used by several investigators to increase the number of mAb-producing hybrids against an antigen and to elicit antibodies specific for poorly immunogenic epitopes. This strategy has implications for vaccine design in that protective immunity is not necessarily directed at immunodominant epitopes of pathogens and could well be improved by shifting a humoral response toward subdominant epitopes. To date, no studies have addressed the potential for immunomodulatory activity mediated by mucosally applied mAbs bound to antigen. To test whether mucosal administration of an exogenous antibody directed against a streptococcal surface protein could influence the humoral immune response, BALB/c mice were immunized orally or intranasally with Streptococcus mutans alone or S. mutans complexed with a mAb directed against the major surface protein P1. S. mutans is a major etiologic against of dental canes and P1 is a promising vaccine antigen. A passively applied anti-P1 mAb has also been reported to prevent recolonization by S. mutans in human subjects, months to years after the exogenous mAb is no longer detectable. Results described in this proposal indicated that binding of an anti-P1 mAb to the surface of S. mutans prior to mucosal immunization causes significant changes in the subclass distribution and specificity of elicited antibodies. Either of these changes has the potential to alter the protective capacity of a humoral immune response. This information is important from the perspective of identifying anti-P1 mAbs which could be used to shift immunodominance toward a more protective response, in addition to providing a plausible explanation for the extremely long clinical effect reported after "passive" immunization of human subjects with an anti-P1 mAb. In that case, exogenous mAb may have complexed with recolonizing S. mutans to modify the adaptive immune response toward one of increased protection. This proposal is designed to screen a panel of twelve well characterized anti-P1 mAbs for immunomodulatory activity in BALB/c mice and to characterize changes in their immune response; to assess the effect of altered murine responses mediated by anti-P1 mAbs on protection against S. mutans using in vitro and in vivo model systems; to directly test serum from mAb-treated human clinical trial patients for changes in their anti-S. mutans response; and lastly to elucidate the mechanism by which anti-P1 mAbs may modulate the immune response against S. mutans. Such information would be directly relevant to the study of any active or passive mucosal immunization strategy.

描述：（根据调查员的摘要改编）：系统性免疫 抗原偶联到单克隆抗体（MAB）已被几种使用 研究人员增加了对A的产生mab产生的杂种数量 抗原并引起针对免疫原性表现不佳的抗体。这 策略对疫苗设计具有影响，因为保护性免疫不是 一定针对病原体的免疫主导表现，很可能是 通过将体液反应转移到亚尺度表位来改善。迄今为止， 没有研究涉及介导的免疫调节活性的潜力 通过与抗原结合的粘膜应用mAb。测试是否粘膜 针对链球菌的外源性抗体的给药 表面蛋白可以影响体液免疫反应，BALB/C小鼠为 单独用链球菌或链球菌或突变链球菌口服或鼻内免疫 与针对主要表面蛋白P1的mAb复合。 S. Mutans 是针对牙齿的主要病因，P1是一种有希望的疫苗 抗原。还报道了被动施用的抗P1 mAB 在人类受试者中进行的S. mutans重殖，几个月至几年 外源性mAb不再可检测到。该提案中描述的结果 表明在 粘膜免疫会导致亚类分布发生重大变化 和引起抗体的特异性。这些更改中的任何一个都有 改变体液免疫反应的保护能力的潜力。这 从识别抗P1 mAB的角度来看，信息很重要 可以用来将免疫施用向更具保护性反应转移 除了为极长的临床提供合理的解释 用抗P1对人类受试者的“被动”免疫后报告的效果 mab。在这种情况下，外源性mAb可能与重新殖民链球菌复合 修改针对增加保护的适应性免疫反应。这 提案旨在筛选一个十二个表征抗P1的面板 mAb在BALB/C小鼠中进行免疫调节活性的mAb，并表征变化 在他们的免疫反应中；评估改变鼠反应的影响 使用抗P1 mAb介导，使用体外和IN保护链球菌的保护 体内模型系统；直接从mab处理的人类临床中测试血清 试验患者的抗S变化。叛变反应；最后 阐明抗P1 mAb可以调节免疫反应的机制 反对叛变。这些信息将与研究直接相关 任何主动或被动粘膜免疫策略。