BLOCKING AUTOANTIBODY SECRETION IN CVID PATIENTS WITH ITP BY IL-2 RESTORED TREGS

描述(由申请人提供)：这项为期五年的提案的首要目标是将候选人发展成为一名独立的调查者，领导在初级免疫缺陷领域的强有力的翻译研究计划。通过他在临床免疫学方面的结构化培训和在人类免疫生物学方面的广泛研究经验，候选人处于最有利的地位，可以充分实现NIH导师职业发展奖的好处。 该提案促进了一系列研究，直接导致引入专门为患有自身抗体介导的自身免疫性疾病的常见变量免疫缺陷患者量身定做的新疗法。这位候选人已经组建了一支杰出的导师团队，他们具有独特的资质，可以帮助实现他的长期研究目标。该团队包括B细胞耐受性领域的先驱Eric Meffre博士、共同变量免疫缺陷国际专家Charlotte Cunningham-Rundles医学博士和在高通量方法方面具有特殊优势的人类遗传学领导者Richard Lifton医学博士。一个不那么正式的咨询委员会，由备受尊敬的医学科学家组成，Pober博士、Hafler博士和Craft博士各自就候选人提案的各个方面提供了建议，并将提供其他持续的科学/职业建议。候选人还提出了一个授课课程和实践经验的计划，旨在促进调查人员在颁奖期结束时的独立性。 研究将集中在调节性T细胞(Treg)对人类自身抗体分泌的抑制。初步数据表明，来自健康捐赠者的Tregs并不直接与B细胞相互作用，而是通过T效应器中介来控制它们。在患有自身免疫性细胞减少症的CVID患者中，由于Treg功能障碍和丰富的循环T效应细胞群(类似滤泡T细胞(TFH))驱动自身抗体的分泌，导致这种控制丧失。该建议的具体目的包括：1)研究Tregs在体外影响B细胞的分子机制；2)确定来自ITP CVID患者的Tfh样细胞在基因表达水平上以及在功能上如何塑造分泌抗体的反应性；以及3)展示IL-2修复的CVID Tregs对Tfh样驱动的自身抗体分泌的影响。总之，该提案的目的是产生临床前数据，以支持对患有自身免疫性红细胞减少的CVID患者进行低剂量IL-2的临床试验。 除了自身的优点外，耶鲁大学免疫生物学、遗传学和儿科提供的理想学术环境和广泛的资源进一步丰富了候选人和他的提议。这位候选人可以通过他自己的耶鲁CVID队列和附近的Cunningham-Rundles博士的CVID队列获得罕见的患者样本，Cunningham-Rundles博士是北美最大的，如果不是世界上最大的。简而言之，这项申请提出了一个相关的、重要的和可实现的研究计划。这是一项旨在最终使候选人在学术环境中建立一个独立的、以患者为中心的研究计划的计划。

DESCRIPTION (provided by applicant): The overarching goal of this five-year proposal is development of the candidate into an independent investigator leading a robust translational research program in the field of primary immune deficiencies. The candidate is optimally positioned, through his background of structured training in clinical immunology and extensive research experience in human immunobiology, to fully realize the benefits of a NIH mentored career development award. The proposal promotes a line of investigation leading directly to the introduction of new therapies specifically tailored for common variable immune deficient patients with autoantibody-mediated autoimmune diseases. The candidate has assembled an outstanding team of mentors uniquely qualified to assist in accomplishing his long-term research goals. The team includes Eric Meffre, PhD, a pioneer in the field of B cell tolerance, Charlotte Cunningham-Rundles, MD PhD, an international expert in common variable immune deficiency and Richard Lifton, MD PhD, a leader in human genetics with specific strength in high-throughput approaches. A less formal advisory committee of highly-regarded medical scientists, Drs. Pober, Hafler and Craft have each advised the candidate on aspects of his proposal and will provide additional ongoing scientific/career advice. The candidate has also proposed a program of didactic coursework and hands-on experiences designed to promote investigator independence at the conclusion of the award period. Research will focus on regulatory T cell (Treg) suppression of autoantibody secretion in humans. Preliminary data suggests that Tregs from healthy donors do not interact with B cells directly but control them through a T effector intermediary. In CVID patients with autoimmune cytopenias there is loss of this control due to Treg dysfunction and the abundance of circulating T effector population, resembling follicular T cells (Tfh), that drives autoantibody secretion. Specific aims of the proposal include: 1) investigating the molecular mechanism employed by Tregs to influence B cells in vitro 2) determining how Tfh-like cells from CVID patients with ITP differ from phenotypicall similar populations in primary ITP patients and healthy donors at the gene expression level and also functionally in terms of how they shape the reactivities of secreted antibodies, and 3) demonstrating the effect of IL-2 restored CVID Tregs on Tfh-like-driven autoantibody secretion. Together the aims of the proposal have been designed to generate pre-clinical data to support a clinical trial of low-dose IL-2 in CVID patients with autoimmune cytopenias. In addition to their own merits, the candidate and his proposal are further enriched by the ideal academic environment and extensive resources provided by Yale University's Departments of Immunobiology, Genetics and Pediatrics. The candidate has access to rare patient samples through his own Yale CVID cohort and the nearby CVID cohort of Dr. Cunningham-Rundles, the largest in North America, if not the world. In brief, this application proposes a plan of research that is relevant, important and achievable. It is a plan designed to culminate in the candidate establishing an independent patient- oriented research program in an academic setting.