IMMUNOMODULATION BY EXOGENOUS STREPTOCOCCAL ANTIBODY

描述：（改编自研究者摘要）：全身免疫 与单克隆抗体（mAb）偶联的抗原已经被几个实验室使用， 研究人员将增加产生mAb的杂交种的数量， 抗原和引发对免疫原性差的表位特异性的抗体。这 策略对疫苗设计有影响，因为保护性免疫不是 必然针对病原体的免疫显性表位， 通过将体液应答向亚显性表位转移而得到改善。到目前为止， 没有研究涉及免疫调节活性介导的可能性 通过粘膜施用的与抗原结合的mAb。为了测试粘膜是否 施用针对链球菌的外源抗体 表面蛋白可影响体液免疫应答，BALB/c小鼠 用单独的变形链球菌或S.变形 与针对主要表面蛋白P1的mAb复合。S.变形 P1是一种很有前途的疫苗 抗原的被动应用抗P1 mAb也可预防 S.人类受试者中的变异体， 外源性mAb不再可检测。本提案中描述的结果 表明抗P1 mAb与S.变形前 粘膜免疫引起亚类分布的显著变化 和引发的抗体的特异性。这两种更改都具有 可能改变体液免疫反应的保护能力。这 从鉴定抗P1 mAb的角度来看， 可用于将免疫优势转向更具保护性的反应， 除了为长期的临床研究提供合理的解释外， 用抗P1抗体“被动”免疫人类受试者后报告的效果 mAb.在这种情况下，外源性mAb可能与磷酸化S复合。变形 以改变适应性免疫反应，使其朝着增强保护的方向发展。这 一项建议是设计来筛选一组12个良好表征的抗P1 mAb在BALB/c小鼠中的免疫调节活性并表征变化 在它们的免疫反应中;评估改变的鼠反应的影响 抗P1单抗介导的抗S.在体外和体内 体内模型系统;以直接测试来自mAb处理的人临床 试验患者的抗S抗体的变化。变种人的反应;最后， 阐明抗P1单克隆抗体调节免疫应答的机制 对于S.变异人这些资料将直接关系到对下列问题的研究： 任何主动或被动粘膜免疫策略。

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.