Defining Initiating Factors Responsible for the Development of FVIII Inhibitors

项目摘要 抗因子(FVIII)同种抗体(抑制物)，可在血友病A患者中发展，限制 为这些患者提供治疗选择，并可能增加发病率和死亡率。然而，并不是所有患有 严重的血友病A会在暴露于FVIII后产生抑制物。预测抑制剂发展的能力 Priori将允许针对高危患者进行预防性干预。然而，目前还没有 能够预测那些在FVIII暴露后会出现抑制剂的患者的方法。此外， 与移植不同的是，即使可以在FVIII暴露之前确定开发出抑制剂的个体，也不会 目前存在的预防策略可以积极地防止抑制剂的形成。不能预测或 预防高危患者的抑制物形成在很大程度上源于对以下方面的根本缺乏了解 启动这一过程的关键途径。我们的长期目标是确定启动机制，然后 协调抑制剂的形成，以预测并预防抗FVIII同种异体抗体的发展 在血友病A患者中，我们的中心假设是边缘带(MZ)B细胞代表一个中心节点。 在启动和协调对FVIII的免疫反应中，因此可能是一个可行的免疫学靶点 对于开发新的策略，不仅要预测，而且要防止抑制剂的形成。我们的假设 是基于我们最近的发现，FVIII在不久之后迅速与MZ B细胞共存 注射和移除MZ B细胞可防止抑制物的形成。AS MZ B细胞和边缘带巨噬细胞 (MZM)具有协同工作的能力，首先捕获循环抗原，然后捕获MZ B细胞介导的 这些初步结果表明，抗原运输到B细胞滤泡和直接激活CD4T细胞 MZ B细胞和MZM可能协同启动FVIII抑制剂的形成。此外，作为MZ B细胞 这些数据表明，在一个特定的个体中，拥有有限和独特的抗体特异性。 在给定的患者中，FVIII特异性MZB细胞前体频率的差异可以预测 血友病A患者在接触FVIII后出现抑制物的可能性。我们将使用 临床和临床前研究的互补方法，将观察数据与机制研究相结合 为了确定MZM和MZB细胞在抑制物形成中的作用，通过测试以下特定目的：AIM 1：确定MZM和MZB细胞在协调FVIII抑制物形成中的作用。目标2：定义 优势抗FVIII MZ B细胞克隆可预测血友病A患者抑制物的形成 成功完成这些目标不仅具备为关键问题提供新的机械性洞察的能力 缓蚀剂形成的方方面面，但也可能建立一个重要的框架，以制定合理的方法 旨在预防性预测并最终防止血友病A患者的抑制物发展。

Project Summary Anti-factor VIII (FVIII) alloantibodies (inhibitors), which can develop in patients with hemophilia A, limit the therapeutic options for these patients, and can increase morbidity and mortality. However, not all patients with severe hemophilia A develop inhibitors following FVIII exposure. The ability to predict inhibitor development a priori would allow prophylactic interventions to be directed toward at-risk patients. However, there is currently no method capable of predicting those patients who will develop inhibitors following FVIII exposure. Furthermore, even if individuals who develop inhibitors could be identified prior to FVIII exposure, unlike transplantation, no prophylactic strategy currently exists that can actively prevent inhibitor formation. The inability to predict or prevent inhibitor formation in at-risk patients largely stems from a fundamental lack of understanding regarding key pathways that initiate this process. 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. Our central hypothesis is that marginal zone (MZ) B cells represent a central node in the initiation and orchestration of immune responses to FVIII, and thus may be a viable immunological target for the development of novel strategies to not only predict, but also prevent inhibitor formation. Our hypothesis is formulated on the basis of our recent discovery that FVIII rapidly co-localizes with MZ B cells shortly after injection and removal of MZ B cells prevents inhibitor formation. As MZ B cells and marginal zone macrophages (MZM) possess the ability to work in concert to initially trap circulating antigen, followed by MZ B cell-mediated trafficking of antigen to the B cell follicle and direct activation of CD4 T cells, these preliminary results suggest that MZ B cells and MZM likely work in concert to initiate FVIII inhibitor formation. Furthermore, as MZ B cells possess a restricted and distinct repertoire of antibody specificities within a given individual, these data suggest that differences in the precursor frequency of FVIII specific MZ B cells within a given patient may predict the likelihood that an individual with hemophilia A will develop inhibitors following FVIII exposure. We will use a complementary approach of clinical and pre-clinical studies to weld observational data with mechanistic studies in order to define the role of MZM and MZ B cells in inhibitor formation by testing the following specific aims: Aim 1: Define the role of MZM and MZ B cells in orchestrating FVIII inhibitor formation. Aim 2: Define the ability of dominant anti-FVIII MZ B cell clones to predict inhibitor formation in patients with hemophilia A. We believe that successful completion of these aims not only possess the capacity to provide new mechanistic insight into key aspects of inhibitor formation, but may also establish an important framework to develop rational approaches designed to prophylactically predict and ultimately prevent inhibitor development in patients with hemophilia A.