IMMUNOMODULATION BY EXOGENOUS STREPTOCOCCAL ANTIBODY

外源链球菌抗体的免疫调节

基本信息

批准号：
6038140
负责人：
L. Jeannine Brady
金额：
$ 24.33万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/6038140
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

项目摘要

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：（改编自研究者的摘要）：全身免疫抗原与单克隆抗体 (mAb) 偶联已被多种药物使用研究人员增加了产生单克隆抗体的杂交体的数量抗原并引发针对免疫原性差的表位的特异性抗体。这策略对疫苗设计有影响，因为保护性免疫并不必然针对病原体的免疫显性表位，并且很可能通过将体液反应转向次优势表位来改善。迄今为止，没有研究探讨免疫调节活性介导的潜力通过粘膜应用与抗原结合的单克隆抗体。测试是否粘膜施用针对链球菌的外源抗体表面蛋白可影响体液免疫反应，BALB/c小鼠单独使用变形链球菌或变形链球菌口服或鼻内免疫与针对主要表面蛋白 P1 的 mAb 复合。变形链球菌是对抗牙杖的主要病因，P1 是一种有前途的疫苗抗原。据报道，被动应用的抗 P1 mAb 也可以预防变形链球菌在人类受试者中重新定植，数月至数年之后不再检测到外源性单克隆抗体。本提案中描述的结果表明抗 P1 mAb 与变形链球菌表面的结合之前粘膜免疫导致亚类分布发生显着变化和引发抗体的特异性。这些变化中的任何一个都具有改变体液免疫反应的保护能力的潜力。这从识别抗 P1 单克隆抗体的角度来看，信息很重要，可以用来将免疫优势转向更具保护性的反应，除了为极其漫长的临床研究提供合理的解释外使用抗 P1 抗体对人类受试者进行“被动”免疫后报告的效果单克隆抗体。在这种情况下，外源性单克隆抗体可能与重新定殖的变形链球菌形成复合物改变适应性免疫反应以增强保护之一。这该提案旨在筛选一组由 12 名特征明确的抗 P1 组成的小组用于 BALB/c 小鼠免疫调节活性并表征变化的单克隆抗体他们的免疫反应；评估小鼠反应改变的影响抗 P1 mAb 介导的体外和体内抗变形链球菌保护作用体内模型系统；直接测试经单克隆抗体处理的人类临床血清试验患者的抗 S 变化。变形反应；最后到阐明抗 P1 mAb 调节免疫反应的机制对抗变形链球菌。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。