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），可以在血友病患者中发展，限制 这些患者的治疗选择，可以增加发病率和死亡率。与大多数免疫原不同 FVIII遇到的宿主遇到，没有典型的先天免疫配体已知可以激活宿主免疫。 尽管如此，在FVIII暴露后，几乎30％的患者会出现抑制剂。无法预防抑制剂 形成很大程度上是由于根本缺乏对FVIII的关键特征的理解 负责参与并激活宿主免疫。我们的长期目标是定义FVIII的关键特征 为了减少或 预防抑制剂的发展。我们的中心假设是FVIII的关键聚糖签名有助于初始宿主 识别和对FVIII的反应，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的 发现不同的FVIII产品不仅具有独特的聚糖签名和独特的诱导能力 抑制剂，以及不同抗FVIII抗体的FVIII参与对宿主免疫细胞的影响不同 互动。这，FVIII聚糖和早期抗FVIII抗体可能代表了关键的早期调节剂 决定FVIII暴露的最终免疫结果。因为独特的聚糖结构可以不同地参与 不同的先天免疫受体，这些结果强烈表明，个体的FVIII糖型可能会有所不同 影响宿主识别和抑制剂开发。此外，不同抗FVIII抗体的能力 抗原呈现细胞的差异影响FVIII的摄取强烈表明性质和表位 早期抗FVIII抗体的特异性可能塑造了随后的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通过自然发生的 抗αGAL抗体，抗αGal抗体（由不同的微生物刺激）也可能结合FVIII并撞击 抑制剂形成的可能性。我们将使用生化分析和体内的完整方法 通过测试以下特定目的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聚糖在抑制剂形成中的作用。目标2：定义抗FVIII抗体在FVIII上的作用 免疫复合物的形成和抑制剂发展。 AIM 3：定义微生物群对抗αGal的影响 抗体发育和随后的抑制剂形成。我们相信这些目标成功完成 不仅具有定义调节抑制剂形成的FVIII关键特征的能力，而且还可以 建立一个重要的框架来开发旨在开发独特FVIII产品的理性方法 免疫原性降低。