IMMUNOMODULATION BY EXOGENOUS STREPTOCOCCAL ANTIBODY

描述：(改编自调查人员摘要)：系统免疫 用抗原偶联的单抗(MAb)已经被几种 调查人员将增加产生单抗的杂交瘤细胞数量 并诱导针对免疫原性较差的表位的抗体。这 策略对疫苗设计有影响，因为保护性免疫不是 必须针对病原体的免疫优势表位，很可能是 通过将体液反应转向次优势表位而得到改进。到目前为止， 还没有研究涉及到免疫调节活性的潜在介导性 通过粘膜应用与抗原结合的单抗。为了测试粘膜是否 注射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 口服或鼻腔单独接种变形链球菌或变形链球菌 与针对主要表面蛋白P1的mAb络合。变形链球菌 是一种主要的牙杖病病原学，P1是一种很有前途的疫苗 抗原。据报道，一种被动应用的抗P1单抗也可以预防 变异链球菌在人类受试者中的重新繁殖，在 不再能检测到外源性单抗。本建议书中描述的结果 结果表明，抗P_1单抗与变形链球菌表面的结合 粘膜免疫引起亚类分布的显著变化 和诱导抗体的特异性。这两个更改中的任何一个都具有 有可能改变体液免疫反应的保护能力。这 从识别抗P1单抗的角度来看，信息是重要的 可以用来将免疫优势转向更具保护性的反应，在 除了为极长的临床试验提供合理的解释之外 用抗P1抗体对受试者进行被动免疫后的效果 Mab.在这种情况下，外源性mAb可能与重新克隆变形链球菌形成了复杂的关系 将适应性免疫反应调整为增强保护的一种。这 该提案旨在筛选12个具有良好特征的抗P1抗体小组 单抗对BALB/c小鼠免疫调节活性的影响及其变化特征 在它们的免疫反应中；评估改变的小鼠反应的效果 抗P1单抗在体外和体内对变形链球菌的保护作用 活体模型系统；直接检测单抗治疗的人临床血清 试验患者的抗S抗体的变化。变种人的反应；最后是 阐明抗P1单抗调节免疫应答的机制 对抗变形链球菌。这些信息将直接与研究 任何主动或被动的粘膜免疫策略。

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.