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: 10680571
• 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/10680571
• 关键词: Address; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Cell Activation; B-Lymphocytes; CD4 Positive T Lymphocytes; Caring; Cells; Clinical; Clinical Research; Collaborations; Coupled; Data; Development; Disease; Environment; Excision; Exhibits; 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 Type I; Interferons; Isoantibodies; Life; Mediating; Mentorship; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Pathway interactions; Patients; Pediatric Hematology; Physicians; Population; Pre-Clinical Model; Process; Public Health; Quality of life; Replacement Therapy; Research; Research Technics; Risk; Risk Factors; Role; Sampling; Scientist; Signal Pathway; Sinus; Spleen; T-Cell Activation; Testing; Therapeutic; Training; Variant; Welding; Work; care costs; career; career development; 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; type I interferon receptor

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/文摘