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: 10117521
• 负责人: Bhavya Sharad Doshi
• 金额: $ 16.2万
• 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/10117521
• 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; 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/antagonist; 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.

项目概要/摘要 K99 血液科学独立职业之路奖详细介绍了一个为期五年的培训计划 推进 Bhavya Doshi 博士成为独立转化医学科学家的职业目标 所提出的应用结合了使用组织培养和动物模型的方法。 使用患者样本进行研究以解决当前对免疫系统理解的局限性 对因子 VIII (FVIII) 的反应 Doshi 博士的职业发展和培训目标旨在促进这一点。 研究提案和她了解导致疾病的基本机制的总体职业目标 制定有针对性的治疗和预防策略 在奖励期间，多西博士将与专家合作。 强大的止血和免疫学科学家团队致力于建立她的免疫学和转化研究 技能，学习她未来职业抱负所需的基因组技能，并继续发展她的专业知识 在她的导师 Rodney Camire 博士和 Michael Milone 博士的指导下， 这些培训目标将通过教学课程和研讨会、参与 系列研讨会、实践研究经验以及咨询委员会的指导。 委员会由具有丰富指导经验和多元化的世界知名科学家组成 他们都擅长将基础研究成果应用于临床。 A 型血友病 (HA) 是由 F8 基因突变导致凝血功能障碍或缺陷引起的 FVIII 的中和抗体（“抑制剂”）的产生是发病和死亡的主要原因。 Doshi 博士对 HA 患者和小鼠的初步研究首次支持了 HA 患者的死亡率。 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 该提案旨在探讨 FVIII 特异性 B 细胞生成的基本机制以及 BAFF 如何产生。 有助于这种体液反应，以便将这些发现用于治疗应用。 试图通过使用一种新的方法来确定小鼠 B 细胞对 FVIII 反应的位置、动力学和类型 识别 FVIII 特异性 B 细胞并随后确定该区室发生情况的方法 免疫调节策略，包括抗 BAFF，因为 BAFF 是由全身和局部产生的。 分别是成纤维细胞和造血来源的免疫细胞，目标 2 研究了 BAFF 及其对 T 细胞对 FVIII 反应的影响最后，目标 3 评估细胞因子的遗传驱动因素。 BAFF 或 T 辅助细胞因子的水平驱动 T 和 B 细胞亚群的表型变化，从而导致抑制剂 这些研究将为免疫区室提供信息。 对 FVIII 免疫反应至关重要，并建立临床前数据以转化抗 BAFF 疗法 该提案中的研究和职业目标将增强多西博士的研究能力 使她能够转变为一名专注于血液疾病，特别是血友病的独立医师科学家。