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） 抗凝血因子VIII（fVIII）同种抗体（抑制剂）可在血友病A患者中产生， 这些患者的治疗选择，并可能增加发病率和死亡率。与大多数免疫原不同 由于fVIII是宿主遇到的免疫原，因此其不具有已知激活宿主免疫的典型先天免疫配体。 尽管如此，近30%的患者在暴露于FVIII后产生抑制物。无法阻止抑制剂 形成很大程度上源于对FVIII的关键特征缺乏了解， 负责激活宿主免疫力我们的长期目标是确定FVIII的关键特征， 其在随后的FVIII暴露后引发然后增强抑制剂形成，以减少或 防止抑制剂形成。我们的中心假设是FVIII上的关键聚糖特征促进初始宿主 识别和应答fVIII，然后形成抗fVIII特异性抗体，反过来影响免疫应答。 后续FVIII暴露的免疫学结果。我们的假设是基于我们最近的 发现不同的FVIII产物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抗体的fVIII参与差异性地影响宿主免疫细胞 交互.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不同程度地 不同的先天免疫受体，这些结果强烈表明，个别fVIII糖型可能差异 影响宿主识别和抑制剂形成。此外，不同的抗-fVIII抗体对免疫原性的影响是不同的。 差异影响抗原呈递细胞对FVIII的摄取，这强烈表明， 早期抗-fVIII抗体的特异性可能形成随后的fVIII暴露的免疫学后果。 最后，由于存在于某些fVIII产物上的非人聚糖表位可以被天然存在的多聚体识别， 抗-αGal抗体、抗-αGal抗体（由不同的微生物群刺激）同样可以结合fVIII并影响 抑制剂形成的可能性。我们将使用生物化学分析和体内实验的互补方法， 通过检测以下特定目的来确定负责抑制剂形成的FVIII关键特征的研究： 目的1：确定fVIII聚糖对抑制剂形成的作用。目的2：定义抗fVIII抗体对fVIII的作用 免疫复合物形成和抑制剂形成。目的3：确定微生物群对抗αGal抗体的影响 抗体发展和随后的抑制剂形成。我们认为，成功实现这些目标， 不仅具有定义调节抑制剂形成的FVIII的关键特征的能力，而且还可以 建立一个重要的框架，以制定合理的方法，旨在开发独特的FVIII产品， 降低免疫原性。