Mechanisms of Immunogenicity of Factor VIII

因子 VIII 的免疫原性机制

• 批准号: 7872019
• 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/7872019
• 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; 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. PUBLIC HEALTH RELEVANCE: Patients with hemophilia A have a deficiency in the blood coagulation protein factor VIII. Some patients with hemophilia A develop antibodies to factor VIII that worsens their bleeding problems and makes therapy difficult and expensive. In this project, we will develop a better understanding of the immune response to the factor VIII protein, which may lead to better treatment alternatives.

描述（由申请人提供）：针对VIII因子（FVIII）的抑制性抗体，大约30％的严重血友病患者响应FVIII的输注而发展。抑制剂的发展与较低的生活质量和增加的经济负担有关，目前被认为是血友病治疗的最重要的并发症。此外，非生物友善的VIII抑制剂可能会发生在非生物友善中，即获得的血友病A，其中可能存在生命和威胁威胁性的并发症。严重血友病A的患者没有循环的FVIII蛋白，因此对FVIII的正常识别为“自我”。因此，免疫系统将治疗性替代FVIII蛋白视为“外来”。鉴于FVIII是一种免疫学上的异物蛋白，因此会出现对FVIII的抗体反应似乎并不奇怪。但是，在啮齿动物和人类中，可溶性蛋白的静脉注射通常无法诱导免疫，并且通常会诱导耐受性态。因此，FVIII的实质免疫原性是出乎意料的。这笔赠款的主要问题是，为什么FVIII会引起免疫反应。该提案中有3个具体目标。 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.在AIM 2中，将构建一个新型的FVIII分子（HOVA），该分子具有插入B结构域中的卵形蛋白的T细胞表位。可用于研究CD4+ T细胞对HOVA静脉输注的CD4+ T细胞反应的机理，可用于研究该T细胞表位的广泛的免疫试剂，包括四聚体试剂和TCR转基因小鼠。有证据表明，在“危险信号”（例如手术或主要出血）时，早期暴露于FVIII会增加抗体发育的风险。在AIM 3中，将通过比较CD4+ T细胞反应与HOVA的静脉输注以及在存在和不存在类似受体的TOLL的情况下的最终抗体产生，从而解决了TOLL像受体激活对FVIII免疫力的作用。这些实验的结果将使对FVIII的实质免疫原性有更深入的了解，并可能为新颖的FVIII分子的未来设计提供了见解，免疫原性降低。该研究计划以及本提案中规定的正式课程和结构化指导应为候选人提供必要的培训，以确立她为独立研究者。 公共卫生相关性：血友病A患者的血液凝结蛋白因子VIII缺乏。一些血友病患者A产生了对VIII因素的抗体，这会使他们的出血问题恶化并使治疗变得困难和昂贵。在这个项目中，我们将更好地了解对VIII因子蛋白的免疫反应，这可能会导致更好的治疗方法。