The Immunobiology of Factor VIII

因子 VIII 的免疫生物学

• 批准号: 10406903
• 负责人: Sean R Stowell
• 金额: $ 37.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406903
• 关键词: Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Binding; Biochemical; Cell Communication; Cells; Data; Development; Epitopes; Exhibits; Exposure to; Factor VIII; Formulation; Glycoproteins; Goals; Hemophilia A; Immune; Immune response; Immunity; Immunobiology; Immunologic Receptors; Immunologics; Individual; Infusion procedures; Injections; Integration Host Factors; Isoantibodies; Ligands; Morbidity - disease rate; Nature; Outcome; Patients; Polysaccharides; Risk; Role; Shapes; Specificity; Structure; Structure-Activity Relationship; Testing; Therapeutic; Welding; base; design; humanized mouse; immunogenicity; in vivo; inhibitor; insight; microbial; microbiota; mortality; patient population; prevent; response; stem; uptake

Summary/Abstract (Project 2) 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. Unlike most immunogens encountered by a host, fVIII possesses no canonical innate immune ligands known to activate host immunity. Despite this, nearly 30% of patients develop inhibitors following fVIII exposure. The inability to prevent inhibitor formation largely stems from a fundamental lack of understanding regarding key features of fVIII that are responsible for engaging and then activating host immunity. Our long-term goal is to define key features of fVIII that initiate and then enhance inhibitor formation following subsequent fVIII exposures, in order to reduce or prevent inhibitor development. Our central hypothesis is that key glycan signatures on fVIII facilitate initial host recognition and response to fVIII, followed by the formation of anti-fVIII specific antibodies that in turn impact the immunological outcome of subsequent fVIII exposures. Our hypothesis is formulated based on our recent discovery that different fVIII products not only possess unique glycan signatures and distinct abilities to induce inhibitors, but also that fVIII engagement by distinct anti-fVIII antibodies differentially impacts host immune cell interactions. Thus, fVIII glycans and early anti-fVIII antibodies may represent key early regulators that dictate the ultimate immune outcome of fVIII exposure. As unique glycan structures can differentially engage distinct innate immune receptors, these results strongly suggest that individual fVIII glycoforms may differentially impact host recognition and inhibitor development. Furthermore, the ability of distinct anti-fVIII antibodies to differentially impact fVIII uptake by antigen presenting cells strongly suggests that the nature and epitope specificity of early anti-fVIII antibodies likely shape the immunological consequence of subsequent fVIII exposure. Finally, as non-human glycan epitopes present on certain fVIII products can be recognized by naturally occurring anti-αGal antibodies, anti-αGal antibodies (stimulated by distinct microflora) may likewise bind fVIII and impact the likelihood of inhibitor formation. We will use a complementary approach of biochemical analyses and in vivo studies to define key features of fVIII responsible for inhibitor formation by testing the following specific aims: Aim 1: Define the role of fVIII glycans on inhibitor formation. Aim 2: Define the role of anti-fVIII antibodies on fVIII immune complex formation and inhibitor development. Aim 3: Define the impact of microbiota on anti-αGal antibody development and subsequent inhibitor formation. We believe that successful completion of these aims not only possesses the capacity to define key features of fVIII that regulate inhibitor formation, but may also establish an important framework to develop rational approaches designed to develop unique fVIII products with reduced immunogenicity.

摘要/摘要（项目 2） 抗因子 VIII (fVIII) 同种抗体（抑制剂）可在 A 型血友病患者中产生，可限制 这些患者的治疗选择可能会增加发病率和死亡率。与大多数免疫原不同 当宿主遇到时，fVIII 不具有已知可激活宿主免疫的典型先天免疫配体。 尽管如此，近 30% 的患者在接触 fVIII 后会产生抑制剂。无法阻止抑制剂 形成很大程度上源于对 fVIII 关键特征的根本缺乏了解 负责参与然后激活宿主免疫力。我们的长期目标是定义 fVIII 的关键特性 在随后的 fVIII 暴露后启动并增强抑制剂的形成，以减少或 防止抑制剂的发展。我们的中心假设是 fVIII 上的关键聚糖特征有利于初始宿主 对 fVIII 的识别和反应，然后形成抗 fVIII 特异性抗体，进而影响 随后的 fVIII 暴露的免疫学结果。我们的假设是根据我们最近提出的 发现不同的 fVIII 产品不仅具有独特的聚糖特征和不同的诱导能力 抑制剂，而且不同的抗 fVIII 抗体与 fVIII 的结合对宿主免疫细胞产生不同的影响 互动。因此，fVIII 聚糖和早期抗 fVIII 抗体可能代表关键的早期调节因子 决定了 fVIII 暴露的最终免疫结果。由于独特的聚糖结构可以差异化地参与 不同的先天免疫受体，这些结果强烈表明个体 fVIII 糖型可能存在差异 影响宿主识别和抑制剂的开发。此外，不同的抗 fVIII 抗体能够 抗原呈递细胞对 fVIII 摄取的不同影响强烈表明，性质和表位 早期抗 fVIII 抗体的特异性可能会影响随后的 fVIII 暴露的免疫学结果。 最后，由于某些 fVIII 产品上存在的非人类聚糖表位可以被天然存在的 抗 αGal 抗体、抗 αGal 抗体（受不同微生物群刺激）同样可能结合 fVIII 并影响 抑制剂形成的可能性。我们将使用生化分析和体内分析的补充方法 通过测试以下具体目标来定义负责抑制剂形成的 fVIII 关键特征的研究： 目标 1：定义 fVIII 聚糖对抑制剂形成的作用。目标 2：定义抗 fVIII 抗体对 fVIII 的作用 免疫复合物的形成和抑制剂的开发。目标 3：确定微生物群对抗 αGal 的影响 抗体的形成和随后的抑制剂形成。我们相信这些目标的成功实现 不仅具有定义调节抑制剂形成的 fVIII 关键特征的能力，而且还可能 建立一个重要的框架来开发合理的方法，旨在开发独特的 fVIII 产品 免疫原性降低。