Blocking autoantibody secretion in CVID patients with ITP by IL-2 restored Tregs

通过 IL-2 阻断 CVID 合并 ITP 患者的自身抗体分泌可恢复 Tregs

• 批准号: 8805484
• 负责人: NEIL David ROMBERG
• 金额: $ 8.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2015-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805484
• 关键词: Address; Advisory Committees; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; Award; B Cell Proliferation; B-Lymphocytes; BLR1 gene; Cell Culture Techniques; Cell physiology; Cell surface; Cells; Characteristics; Chronic; Clinical; Clinical Data; Clinical Immunology; Clinical Trials; Coculture Techniques; Data; Defect; Deficiency Diseases; Development; Disease; Doctor of Philosophy; Dose; Environment; Functional disorder; Gene Expression; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Goals; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Human Genetics; Immune; Immunobiology; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; In Vitro; Interleukin-10; Interleukin-2; Interleukin-4; Interleukins; International; Investigation; K-Series Research Career Programs; Maintenance; Measures; Mediating; Medical; Memory B-Lymphocyte; Mentors; Molecular; Morbidity - disease rate; Mus; North America; Nuclear; Outcome; PAX5 gene; PRDM1 gene; Patients; Pediatrics; Plasma Cells; Plasmablast; Population; Positioning Attribute; Prevalence; Production; Prophylactic treatment; Qualifying; Regulatory T-Lymphocyte; Replacement Therapy; Research; Research Personnel; Resources; Role; Sampling; Scientist; Serum; Shapes; Structure; Surface; T-Lymphocyte; Thrombocytopenia; Training; Transcript; Translating; Translational Research; United States National Institutes of Health; Universities; Work; autoreactive B cell; career; chemokine receptor; cohort; common treatment; conditioning; cytokine; cytopenia; design; experience; improved; interest; killings; mortality; patient oriented research; peripheral blood; plasma cell differentiation; pre-clinical; programs; public health relevance; research study; response; therapy development

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.

描述（由申请人提供）：该五年提案的总体目标是将候选人发展成为一名独立研究者，领导原发性免疫缺陷领域的强大转化研究项目。通过临床免疫学的结构化培训背景和人类免疫生物学的丰富研究经验，候选人处于最佳位置，可以充分实现 NIH 指导的职业发展奖的好处。 该提案促进了一系列研究，直接导致引入专门针对患有自身抗体介导的自身免疫性疾病的常见变异免疫缺陷患者的新疗法。该候选人组建了一支优秀的导师团队，他们具有独特的资格来协助他实现长期研究目标。该团队包括 B 细胞耐受领域的先驱 Eric Meffre 博士、常见变异免疫缺陷领域的国际专家 Charlotte Cunningham-Rundles 医学博士和在高通量方法方面具有特殊实力的人类遗传学领域的领导者 Richard Lifton 医学博士。一个不太正式的咨询委员会，由备受尊敬的医学科学家组成，博士。波伯、哈夫勒和克拉夫特分别就候选人提案的各个方面向候选人提供了建议，并将提供额外的持续科学/职业建议。候选人还提出了一个教学课程和实践经验计划，旨在在奖励期结束时促进研究者的独立性。 研究将集中于抑制人类自身抗体分泌的调节性 T 细胞 (Treg)。初步数据表明，来自健康供体的 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。在患有自身免疫性血细胞减少症的 CVID 患者中，由于 Treg 功能障碍和循环 T 效应细胞群（类似于滤泡 T 细胞 (Tfh)）的丰富，导致自身抗体分泌而失去这种控制。该提案的具体目标包括：1）研究Tregs在体外影响B细胞的分子机制2）确定来自患有ITP的CVID患者的Tfh样细胞与原发性ITP患者和健康供体中表型相似的细胞群在基因表达水平上有何不同，以及它们如何影响分泌抗体的反应性，以及3）证明IL-2恢复的CVID Tregs对 Tfh 样驱动的自身抗体分泌。该提案的共同目标是生成临床前数据，以支持在患有自身免疫性血细胞减少症的 CVID 患者中进行低剂量 IL-2 的临床试验。 除了自身的优点外，耶鲁大学免疫生物学、遗传学和儿科系提供的理想的学术环境和广泛的资源进一步丰富了候选人及其提案。候选人可以通过他自己的耶鲁大学 CVID 队列和附近的 Cunningham-Rundles 博士的 CVID 队列获得稀有患者样本，该队列是北美乃至全球最大的 CVID 队列。简而言之，本申请提出了一项相关、重要且可实现的研究计划。该计划旨在最终使候选人在学术环境中建立独立的以患者为导向的研究计划。