Mechanistic insights into factor VIII inhibitor formation and eradication

对因子 VIII 抑制剂形成和根除的机制见解

• 批准号: 10413819
• 负责人: Bhavya Sharad Doshi
• 金额: $ 15.8万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413819
• 关键词: Acquired Immunodeficiency Syndrome; Address; Advisory Committees; Affinity; Animal Model; Antibodies; Antibody Response; Antibody Therapy; Antigens; Autoimmune Diseases; Award; B-Lymphocyte Subsets; B-Lymphocytes; Basic Science; Biological Markers; Blood; Blood Coagulation Disorders; Bypass; CD4 Positive T Lymphocytes; Career Choice; Cell Maturation; Cells; Chronic; Clinic; Coagulation Factor Deficiency; Coagulation Process; Cytokine Gene; Data; Dendritic Cells; Dependence; Development; Disease; Dose; Educational workshop; Equilibrium; F8 gene; Factor VIII; Fibroblasts; Fostering; Functional disorder; Future; Generations; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Helper-Inducer T-Lymphocyte; Hematological Disease; Hematopoietic; Hemophilia A; Hemorrhage; Hemostatic function; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Immunologics; Immunology; In Vitro; Infusion procedures; Inherited; Interleukin-10; Investigation; Isoantibodies; Joints; Kinetics; Lead; Learning; Location; MS4A1 gene; Marrow; Mature B-Lymphocyte; Memory; Memory B-Lymphocyte; Mentors; Methods; Morbidity - disease rate; Mus; Mutation; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Plasma Cells; Population; Predisposing Factor; Prevention strategy; Proliferating; Quality of life; Research; Research Proposals; Role; Sampling; Science; Scientist; Secondary to; Series; Source; Structure of germinal center of lymph node; Susceptibility Gene; T cell response; T-Lymphocyte; TNF gene; Therapeutic; Training; Training Programs; Translating; Translational Research; Variant; Work; anti-CD20; antibody inhibitor; arthropathies; belimumab; biobank; career; career development; cytokine; enzyme replacement therapy; experience; hands on research; immunogenicity; immunomodulatory strategy; immunomodulatory therapies; improved; in vivo; inhibitor; inhibitor therapy; insight; member; mortality; mouse model; neutralizing antibody; novel; novel marker; pre-clinical; predictive marker; prevent; recruit; response; secondary lymphoid organ; skills; targeted treatment; tissue culture; translational physician; treatment strategy

PROJECT SUMMARY/ABSTRACT This K99 Career Pathway to Independence in Blood Science Award details a five-year training program to advance Dr. Bhavya Doshi’s career goal of becoming an independent translational physician-scientist in coagulation. The proposed application combines approaches using tissue culture and animal models with investigations using patient samples to address the current limitations in the understanding of the immune response to factor VIII (FVIII). Dr. Doshi’s career development and training objectives are geared to foster this research proposal and her overall career goal of understanding basic mechanisms that drive disease to develop targeted treatment and prevention strategies. During the award period, Dr. Doshi will engage with a robust team of scientists in hemostasis and immunology to build her immunologic and translational research skills, learn genomic skills necessary for her future career aspirations, and continue to develop her expertise in coagulation and inhibitors. Under the guidance of her mentors, Dr. Rodney Camire and Dr. Michael Milone, these training objectives will be met by a combination of didactic course work and workshops, participation in seminar series, hands-on research experience, and mentoring by her advisory committee. Her advisory committee is composed of world-renowned scientists with extensive mentoring experience and diverse and complementary scientific expertise. They are all versed in bringing basic research findings to the bedside. Hemophilia A (HA) is caused by a mutation in the F8 gene leading to dysfunction or deficiency of coagulation FVIII. The development of neutralizing antibodies (“inhibitors”) to FVIII is the leading cause of morbidity and mortality in patients with HA. Dr. Doshi’s preliminary studies in HA patients and mice are the first to support that the cytokine B cell activating factor (BAFF) is potentially a biomarker and/or regulator of the FVIII immune response. This proposal seeks to probe basic mechanisms in FVIII-specific B cell generation and how BAFF contributes to this humoral response in order to leverage these findings for therapeutic application. Aim 1 seeks to determine the location, kinetics, and types of B cell responses to FVIII in mice by using a novel method to identify FVIII-specific B cells and subsequently determine what happens to this compartment with immunomodulatory strategies, including anti-BAFF. As BAFF is both systemically and locally produced by fibroblast cells and hematopoietically-derived immune cells, respectively, Aim 2 investigates the source of BAFF and its effect on the T cell response to FVIII. Finally, Aim 3 assesses whether genetic drivers of cytokine levels for BAFF or T helper cytokines drive phenotypic changes in T and B cell subsets that lead to inhibitor generation and/or persistence in HA patients. Together, these studies will inform the immune compartments that are critical to the FVIII immune response and establish the preclinical data to translate anti-BAFF therapy to the clinics. The research and career objectives in this proposal will bolster Dr. Doshi’s research repertoire to enable her transition to an independent physician scientist focused on blood disorders, specifically hemophilia.

项目摘要/摘要 K99血液科学独立职业道路奖详细介绍了一项为期五年的培训计划，以 推进Bhavya Doshi博士的职业目标，即成为一名独立的翻译内科医生-科学家 凝结。拟议的应用程序将使用组织培养和动物模型的方法与 使用患者样本进行调查，以解决目前对免疫理解的局限性 对因子VIII(Fviii)的反应。Doshi博士的职业发展和培训目标就是为了促进这一点 研究提案和她的总体职业目标是了解驱动疾病的基本机制 制定有针对性的治疗和预防战略。在颁奖期间，Doshi博士将与一位 强大的止血和免疫学科学家团队，建立她的免疫学和翻译研究 技能，学习她未来职业抱负所需的基因组技能，并继续发展她在 凝血和抑制剂。在她的导师罗德尼·卡米雷博士和迈克尔·米隆博士的指导下， 这些培训目标将通过教学课程工作和研讨会相结合的方式实现，参与 系列研讨会，实践研究经验，以及她的顾问委员会的指导。她的建议 委员会由世界知名的科学家组成，他们具有丰富的指导经验和多样化的 相互补充的科学专门知识。他们都精通于将基础研究成果带到床边。 血友病A(HA)是由F8基因突变导致的功能障碍或凝血功能缺陷引起的 Fviii.FVIII的中和抗体(“抑制物”)的产生是发病和 HA患者的死亡率。Doshi博士在HA患者和小鼠身上的初步研究首次支持 细胞因子B细胞激活因子(BAFF)可能是FVIII免疫的生物标志物和/或调节因子 回应。这项建议试图探索FVIII特异性B细胞产生的基本机制以及BAFF是如何 有助于这种体液反应，以便利用这些发现进行治疗应用。目标1 试图通过使用一种新的方法来确定小鼠对FVIII的B细胞反应的位置、动力学和类型 方法来鉴定FVIII特异性B细胞，并随后确定这个隔室发生了什么 免疫调节策略，包括抗BAFF。由于BAFF是由以下公司系统和本地生产的 成纤维细胞和造血源免疫细胞，Aim 2分别研究了 BAFF及其对T细胞对FVIII反应的影响。最后，Aim 3评估了细胞因子的遗传驱动因素 BAFF或T辅助细胞因子水平驱动T和B细胞亚群的表型变化导致抑制物 HA患者的生成和/或持久性。总而言之，这些研究将告知免疫隔间 对FVIII免疫反应至关重要，并建立了转化抗BAFF治疗的临床前数据 去诊所。该提案中的研究和职业目标将支持Doshi博士的研究曲目 使她成为一名专注于血液疾病，特别是血友病的独立内科科学家。