Investigating the Effect of Antibody Mediated Feedback on B Cell Clonal Selection

项目总结/摘要 由感染或疫苗接种引起的高亲和力抗体滴度形成防止再感染的基础。 然而，预先存在的抗原特异性滴度也与次级B细胞反应减弱有关 相同的抗原。这个概念，称为抗体介导的反馈，仍然没有得到很好的定义， 机械水平。抗体反馈在B细胞克隆选择中的作用机制及结果 需要开发针对重复遇到的保守表位的免疫策略， 进化的病原体 为了在生理环境中研究抗体介导的反馈，我建议开发寡克隆B细胞 对流感血凝素上不同表位仅有三种特异性的过继转移小鼠模型 （民政事务局）。在我的初步工作中，我已经描述了三种单克隆抗体的特征，它们结合到 HA.与此同时，我还通过基因工程消除了浆细胞。结合这两种模式 将允许从具有简化的B细胞库的系统中去除一种特异性的免疫球蛋白。 观察去除特异性抗体后B细胞克隆选择的结果将提供对以下方面的了解： 抗体介导反馈的精确机制。 我是威尔康奈尔/纪念斯隆凯特琳/洛克菲勒三机构计划的医学博士/博士生， 在洛克菲勒大学Gabriel Victora博士的实验室进行拟议的研究。我 长期目标是成为一名医生科学家谁平衡病人护理与运行独立的 在学术机构的研究项目。该提案中概述的计划，沿着的支持和 导师由Victora博士，Nussenzweig博士，我的论文研究委员会和三机构提供 管理学院将帮助我实现我的职业目标。

Project Summary/Abstract High affinity antibody titers elicited by infection or vaccination form the basis for protection against reinfection. However, preexisting antigen-specific titers are also associated with diminished secondary B cell responses to the same antigen. This concept, termed antibody mediated feedback, remains poorly defined at the mechanistic level. Elucidation of the mechanisms and outcomes of antibody feedback on B cell clonal selection is required to develop immunization strategies that target conserved epitopes on repeatedly encountered evolving pathogens. To study antibody mediated feedback in a physiologic setting, I propose to develop an oligoclonal B cell adoptive transfer mouse model with only three specificities to different epitopes on influenza hemagglutinin (HA). In my preliminary work, I have characterized three monoclonal antibodies that bind to distinct sites on HA. In parallel, I have genetically engineered the ability to delete plasma cells. Combining these two models will allow for the removal of immunoglobulin of one specificity from a system with a simplified B cell repertoire. Observing the outcomes of B cell clonal selection upon removal of specific antibodies will provide insight into the precise mechanism by which antibody mediated feedback operates. I am an MD/PhD student at the Weill Cornell/Memorial Sloan Kettering/Rockefeller Tri-Institutional Program, performing the proposed research in the laboratory of Dr. Gabriel Victora at The Rockefeller University. My long-term goal is to become a physician scientist who balances patient care with running an independent research program at an academic institution. The plan outlined in this proposal, along with the support and mentorship provided by Dr. Victora, Dr. Nussenzweig, my thesis research committee, and the Tri-Institutional administrative faculty will help me achieve my career goals.