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: 10482349
• 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/10482349
• 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; 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.

项目摘要/摘要 抗因子(FVIII)同种异体抗体，称为抑制物，在20%-30%的重症患者中产生 血友病A用FVIII输液治疗后。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，生活质量下降。尽管 抑制剂形成的负面后果，目前还没有预防性治疗可以预测或预防 抑制剂开发。这在很大程度上是因为对关键途径缺乏根本的了解， 启动这一过程。为了有效地了解可能预测抑制剂可能性的危险因素 在高危患者中发展并防止这一过程，我们的长期目标是确定其机制 启动并随后协调抑制剂的形成，以预测并随后防止抗- 血友病A患者中的FVIII同种异体抗体这与NHLBI确定的关键优先事项一致 确定可用于防止抑制物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表明，两者的耗竭 边缘带(MZ)B细胞和I型干扰素受体(IFNRs)基因缺失显著减少 FVIII暴露后形成同种异体抗体。因此，MZ B细胞和I型IFN代表关键的启动 抑制剂开发的途径。进一步的假设是I型干扰素(IFN)直接 增强FVIII特异性MZ B细胞产生抗FVIII抗体的能力，运输抗原到B细胞 在FVIII暴露后，卵泡和直接激活的CD4T细胞，以及使用抑制剂的患者表现出 增强的I型干扰素基因特征。使用临床和临床前模型，第一个目标是定义 I型干扰素在FVIII暴露后MZ B细胞介导抗体形成中的作用及I型干扰素的测定 血友病A患者使用和不使用抑制剂时的干扰素签名。第二个目标集中在定义 I型干扰素在MZ B细胞抗原转运和CD4T细胞活化中的作用这些研究拥有 不仅提供了对缓蚀剂形成的关键方面的新见解，而且还可能提供重要的 制定合理方法的框架，以预防性地预测和预防 血友病患者A。 除了上面概述的重要研究目标外，这项建议还将允许高级指导 与血液学领域相关的免疫学以及包括核糖核酸在内的新研究技术的培训 测序和人体样本处理。这将在一个有声望的学者的环境中进行 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地成为一名独立医生。 科学家，将儿科血液病患者的护理与该领域的持续进步相结合。