Mechanisms of Immunogenicity of Factor VIII

因子 VIII 的免疫原性机制

• 批准号: 8433364
• 负责人: Shannon L. Meeks
• 金额: $ 12.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433364
• 关键词: A Mouse; A-factor (Streptomyces); Address; Adoptive Transfer; Affect; Agonist; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Area; B-domain-deleted factor VIII; Biological; Biological Models; Blood coagulation; Bypass; CD4 Positive T Lymphocytes; Carrier Proteins; Coagulation Process; Complication; Conflict (Psychology); Development; Economic Burden; Event; Exposure to; Factor VIII; Frequencies; Future; Generations; Genes; Grant; Hemophilia A; Hemorrhage; Human; Imagery; Immune response; Immune system; Immunity; Immunization; Immunologics; Inflammation; Infusion procedures; Intravenous; Intravenous infusion procedures; Lead; Life; Limb structure; Lipopolysaccharides; Lymphatic; Mentorship; Modeling; Morbidity - disease rate; Mus; Mutation; Operative Surgical Procedures; Ovalbumin; Patients; Phenotype; Physiological; Poly I-C; Population; Proteins; Quality of life; Reagent; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Risk; Rodent; Role; Signal Transduction; Site; Specificity; Structure; T cell response; T-Cell Activation; T-Lymphocyte Epitopes; Technology; Testing; Therapeutic; Thrombin; Time; Time Factors; Toll-like receptors; Training; Transgenic Mice; Treatment Cost; alternative treatment; antibody inhibitor; cytokine; design; human F8 protein; immune self tolerance; immunogenic; immunogenicity; in vivo; inhibitor/antagonist; insight; intravenous injection; memory CD4 T lymphocyte; non-genetic; novel; programs; public health relevance; recombinant antihemophilic factor VIII; research study; response; tool; trafficking; von Willebrand Factor

DESCRIPTION (provided by applicant): Inhibitory antibodies to factor VIII (fVIII) develop in approximately 30% of patients with severe hemophilia A in response to infusions of fVIII. Inhibitor development is associated with a lower quality of life and an increased economic burden and is currently is considered the most significant complication of the management of hemophilia A. Additionally, factor VIII inhibitors can occur in nonhemophiliacs, i.e. acquired hemophilia A, in which there can be life and limb- threatening complications. Patients with severe hemophilia A have no circulating fVIII protein and thus normal recognition of fVIII as "self" does not develop. Accordingly, the therapeutic replacement fVIII protein is seen as "foreign" by the immune system. Given that fVIII is an immunologically foreign protein, it may not seem surprising that an antibody response to fVIII would occur. However, in both rodents and humans, intravenous injection of soluble proteins usually fails to induce immunity and often induces a tolerogenic state. For this reason, the substantial immunogenicity of fVIII is unexpected. The central question of this grant is why, and by what mechanism, does fVIII induce an immune response. There are 3 Specific Aims in this proposal. In Aim 1, the role of the physiological site of fVIII presentation to the immune system, i.e. a site of inflammation where a clot is forming and where fVIII is released from its large carrier protein von Willebrand factor, will be characterized by comparing the immunogenicity of fVIII with an inactive form of fVIII in a murine hemophilia A immunogenicity model. In Aim 2, a novel fVIII molecule (HOVA) will be constructed that has a well characterized T cell epitope of ovalbumin inserted into the B domain. A wide array of immunologic reagents specific for this T cell epitope, including tetramer reagents and TCR transgenic mice, are available to investigate the mechanism of CD4+ T cell response to intravenous infusion of HOVA. There is evidence that early exposure to fVIII at the time of a "danger signal" such as surgery or a major bleed increases the risk of antibody development. In Aim 3 the role of toll like receptor activation on fVIII immunity will be addressed by comparing the CD4+ T cell response to intravenous infusion of HOVA as well as the ultimate antibody production in the presence and absence of toll like receptor agonists. The results of these experiments will allow for a deeper understanding of the substantial immunogenicity of fVIII and might provide insights for future design of novel fVIII molecules with decreased immunogenicity. This research plan along with the formal coursework and structured mentorship laid out in this proposal should provide the candidate with the training necessary to establish her as an independent investigator.

描述（由申请方提供）：大约30%的重度血友病A患者在输注fVIII后产生了因子VIII（fVIII）抑制性抗体。抑制物形成与生活质量降低和经济负担增加相关，目前被认为是血友病A治疗的最重要并发症。此外，因子VIII抑制剂可发生在非血友病患者中，即获得性血友病A，其中可存在危及生命和肢体的并发症。重度血友病A患者没有循环中的fVIII蛋白，因此不能将fVIII正常识别为“自身”。因此，治疗性替代fVIII蛋白被免疫系统视为“外来的”。由于FVIII是一种免疫学外源蛋白，因此发生对FVIII的抗体应答似乎并不奇怪。然而，在啮齿类动物和人类中，静脉注射可溶性蛋白通常不能诱导免疫，并且通常诱导致耐受性状态。因此，FVIII的显著免疫原性是出乎意料的。这项资助的核心问题是，为什么以及通过什么机制，fVIII诱导免疫应答。这个提案有三个具体目标。在目的1中，将通过比较fVIII的免疫原性来表征fVIII提呈免疫系统的生理位点的作用，即血栓形成和fVIII从其大载体蛋白von Willebrand因子中释放的炎症位点。小鼠血友病A免疫原性模型中的非活性形式的fVIII。在目标2中，将构建新的fVIII分子（霍瓦），其具有插入到B结构域中的充分表征的卵清蛋白的T细胞表位。多种对该T细胞表位具有特异性的免疫试剂，包括四聚体试剂和TCR转基因小鼠，可用于研究CD 4 + T细胞对静脉输注霍瓦的反应机制。有证据表明，在手术或大出血等“危险信号”出现时，早期暴露于FVIII会增加抗体产生的风险。在目的3中，将通过比较CD4+ T细胞对静脉输注霍瓦的应答以及在存在和不存在toll样受体激动剂的情况下的最终抗体产生来说明toll样受体活化对fVIII免疫的作用。这些实验的结果将允许对FVIII的实质免疫原性有更深入的了解，并可能为未来设计具有降低的免疫原性的新型FVIII分子提供见解。本研究计划沿着正式课程和结构化指导，应提供候选人必要的培训，以建立她作为一个独立的调查员。