The Role of Type I Interferons in Factor VIII Inhibitor Formation

I 型干扰素在因子 VIII 抑制剂形成中的作用

• 批准号: 10301610
• 负责人: Patricia Elizabeth Zerra
• 金额: $ 15.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301610
• 关键词: Address; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Cell Activation; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Caring; Cells; Clinical; Clinical Research; Collaborations; Coupled; Data; Development; Disease; Environment; Excision; Exhibits; F8 gene; Factor VIII; Failure; Genetic; Goals; Hematology; Hemophilia A; Hemorrhage; Human; Immune; Immune Targeting; Immune response; Immunology; Individual; Infusion procedures; Injections; Institution; Instruction; Interferon Activation; Interferon Receptor; Interferon Type I; Interferons; Isoantibodies; Life; Mediating; Mentorship; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Pathway interactions; Patients; Pediatric Hematology; Physicians; Play; Population; Pre-Clinical Model; Process; Public Health; Quality of life; Replacement Therapy; Research; Research Technics; Risk; Risk Factors; Role; Sampling; Savings; Scientist; Signal Pathway; Sinus; Spleen; T-Cell Activation; Testing; Therapeutic; Training; Variant; Welding; Work; care costs; career; career development; cell type; cytokine; genetic signature; improved; inhibitor/antagonist; insight; mortality; mouse model; novel; pre-clinical; preclinical study; prevent; prophylactic; receptor; research and development; response; side effect; stem; therapeutic target; trafficking; transcriptome sequencing

Project Summary/Abstract Anti-factor VIII (FVIII) alloantibodies, known as inhibitors, develop in 20-30% of patients with severe hemophilia A following therapy with FVIII infusion. This, in turn, makes bleeding difficult to control and prevent, resulting in increased morbidity and mortality, increased cost of care and decreased quality of life. Despite the negative consequences of inhibitor formation, no prophylactic therapy is currently available to predict or prevent inhibitor development. This largely stems from a fundamental lack of understanding regarding key pathways that initiate this process. In order to effectively understand risk factors that may predict the likelihood of inhibitor development and then prevent this process in at-risk patients, our long-term goal is to identify the mechanisms that initiate and then orchestrate inhibitor formation, in order to predict and then prevent the development of anti- FVIII alloantibodies in patients with hemophilia A. This is in line with a key priority identified by the NHLBI to identify key immune targets that may be used to prevent inhibitor formation. Addressing these pertinent clinical problems, recent data in a pre-clinical model shows that both depletion of marginal zone (MZ) B cells and genetic deletion of type I IFN receptors (IFNRs) significantly reduces alloantibody formation following FVIII exposure. Thus, MZ B cells and type I IFNs represent key initiating pathways for inhibitor development. The hypothesis moving forward is that type I interferons (IFNs) directly enhance the ability of FVIII-specific MZ B cells to generate anti-FVIII antibodies, traffic antigen to the B cell follicle, and directly activate CD4 T cells following FVIII exposure and that patients with inhibitors display an enhanced type I IFN gene signature. Using both a clinical and pre-clinical model, the first aim is to define the role of type I IFNs on MZ B cell-mediated antibody formation following FVIII exposure and determine the type I IFN signature in patients with hemophilia A with and without inhibitors. The second aim focuses on defining the role of type I IFNs on MZ B cell antigen trafficking and activation of CD4 T cells. These studies possess the capacity to not only provide new insight into key aspects of inhibitor formation, but may also provide an important framework to develop rational approaches to prophylactically predict and prevent inhibitor development in patients with hemophilia A. In addition to the important research aims outlined above, this proposal will allow for advanced instruction in immunology relevant to the field of hematology as well as training in novel research techniques including RNA sequencing and human sample processing. This will take place in the environment of a prestigious academic institution with many opportunities for collaboration and mentorship. Completion of the outlined research and career development goals will facilitate successful advancement to a career as an independent physician scientist, combining the care of pediatric hematology patients with continued advancements in the field.

项目总结/摘要 抗凝血因子VIII（FVIII）同种抗体，称为抑制剂，在20-30%的重度 FVIII输注治疗后的血友病A。这反过来又使出血难以控制和预防， 导致发病率和死亡率增加、护理费用增加和生活质量下降。尽管 抑制剂形成的负面后果，目前没有预防性治疗可用于预测或预防 抑制剂开发。这在很大程度上源于对关键途径的根本缺乏了解， 启动这个过程。为了有效地了解可能预测抑制剂可能性的风险因素， 发展，然后在高危患者中预防这一过程，我们的长期目标是确定机制， 启动并协调抑制剂的形成，以预测并防止抗- 血友病A患者的FVIII同种抗体这符合《国家HLBI》确定的关键优先事项， 确定可用于防止抑制剂形成的关键免疫靶点。 为了解决这些相关的临床问题，临床前模型中的最新数据显示， 边缘区（MZ）B细胞的生长和I型IFN受体（IFNRs）的基因缺失显着减少 FVIII暴露后同种抗体形成。因此，MZ B细胞和I型干扰素代表了启动 抑制剂发展的途径。向前发展的假设是，I型干扰素（IFN）直接 增强FVIII特异性MZ B细胞产生抗FVIII抗体、运输抗原至B细胞的能力 卵泡，并直接激活CD 4 T细胞后，FVIII暴露和抑制剂的患者显示， 增强的I型IFN基因签名。使用临床和临床前模型，第一个目标是定义 FVIII暴露后I型IFN对MZ B细胞介导的抗体形成的作用，并确定I型IFN 有和没有抑制剂的血友病A患者的IFN特征第二个目标是确定 I型IFN对MZ B细胞抗原运输和CD 4 T细胞活化的作用。这些研究拥有 这种能力不仅可以为抑制剂形成的关键方面提供新的见解，而且还可以提供重要的 框架，以制定合理的方法来预测和防止抑制剂的发展， 血友病A患者。 除了上述重要的研究目标外，该提案还将允许高级教学 在与血液学领域相关的免疫学以及包括RNA在内的新研究技术方面的培训 测序和人类样本处理。这将发生在一个著名的学术环境中， 这是一个有很多合作和指导机会的机构。完成概述的研究和 职业发展目标将有助于成功晋升为独立医生 科学家，结合儿科血液病患者的护理与该领域的持续进步。