EPITOPES OF ANTIFACTOR VIII ANTIBODIES IN HEMOPHILIACS

血友病患者中抗因子 VIII 抗体的表位

• 批准号: 2714110
• 负责人: DOROTHEA H SCANDELLA
• 金额: $ 22.81万
• 依托单位: AMERICAN NATIONAL RED CROSS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2714110
• 关键词: B lymphocyte; T lymphocyte; activation product; affinity chromatography; antibody formation; antibody neutralization test; anticoagulants; antiidiotype antibody; binding proteins; chimeric proteins; clinical research; coagulation factor VIII; conformation; epitope mapping; hemophilia As; human subject; immune tolerance /unresponsiveness; immunoprecipitation; infant human (0-1 year); inhibitor /antagonist; molecular site; protein structure function; radioimmunoassay; swine; synthetic peptide

DESCRIPTION: This is a new proposal which is a logical extension of the PI's past work describing clinically important antibodies to factor VIII in hemophiliacs. Human antibodies that inactivate blood coagulation factor VIII (FVIII inhibitors) develop in up to 37% of repeatedly transfused patients with severe hemophilia A. Although the effects of inhibitors are variable, significant bleeding and disability are frequent, and they are responsible for a large proportion of the cost of hemophilia care. There is no generally satisfactory approach to this problem. Detailed knowledge of the characteristics of FVIII specific T and B cells as well as the spectrum of the anti-FVIII antibodies is essential for the establishment of in vitro and in vivo studies of the immune response to FVIII and how it might be eliminated. The long term goal is to identify all anti-FVIII antibodies in hemophilic inhibitor patients. During the past 6 years, the applicant have pioneered the use of recombinant FVIII-derived polypeptides to localize the epitopes and to identify the inhibitory functions of anti-FVIII antibodies. They found that most patient plasmas contain anti-A2 and anti-C2 domain antibodies which are inhibitors of FVIII activity, and we have determined their mechanisms of FVIII inactivation. Their data from inhibitor neutralization assays suggest that as few as 3 different antibodies may account for the inhibitor titer in >90% of patients. They will determine if there are human antibodies which bind to the remaining FVIII domains A1, B, A3, and C1, if they inhibit FVIII activity, and what their mechanisms of inactivation are. The epitopes of the major inhibitors will be further localized. This information may suggest how mutant FVIII proteins which are fully active but unresponsive to inhibitors can be designed for patient therapy. They have developed immunoprecipitation assays which can detect anti-FVIII antibody levels 100-fold lower that those that are found in patients who have clinically significant inhibitors. The early immune response to FVIII in infant hemophiliacs will be examined to establish if one can predict which ones are tolerant and which ones will form antibodies to infused FVIII. It may be beneficial to initiate treatment to eradicate the anti-FVIII antibodies before they become a clinical problem. This possibility was suggested by a large, international study in which tolerance induction was most successful when it was begun while the inhibitor titer was low. For those patients who become tolerant after appearance of an inhibitor, it will be determined if this is due to antibody disappearance and/or to the appearance of additional noninhibitory antibodies. The presence of new antibodies in tolerant patients has been previously reported but their relationship to the tolerant state was not elucidated.

描述：这是一个新建议，是该提案的逻辑扩展 Pi过去的工作描述了临床上重要的抗体， 血友病。 使血液凝血因子失活的人类抗体 VIII（FVIII抑制剂）在多达37％的反复输血中发展 严重的血友病患者A.尽管抑制剂的作用是 可变，明显的出血和残疾经常出现，它们是 负责大部分血友病护理费用。 有 对于这个问题，通常没有令人满意的方法。 详细的知识 FVIII特异性T和B细胞的特征以及光谱 抗FVIII抗体的体外至关重要 以及对FVIII免疫反应及其可能如何的体内研究 淘汰。 长期目标是确定所有抗FVIII抗体 血友病患者。 在过去的6年中，申请人有 率先使用重组FVIII衍生的多肽来定位 表位并确定抗FVIII抗体的抑制作用。 他们发现大多数患者等离子体都包含抗A2和抗C2结构域 是FVIII活性抑制剂的抗体，我们已经确定 他们的FVIII灭活机制。 他们来自抑制剂的数据 中和测定表明，只有3种不同的抗体可能 在> 90％的患者中解释抑制剂滴度。 他们将确定是否 有人类抗体与其余的FVIII结构域A1，B， A3和C1，如果它们抑制FVIII活性，以及​​它们的机制 失活是。 主要抑制剂的表位将进一步 本地化。 这些信息可能表明突变的FVIII蛋白如何 完全活跃但对抑制剂的反应无反应 治疗。 他们开发了可以检测到的免疫沉淀测定法 抗FVIII抗体水平比在 具有临床意义抑制剂的患者。 早期免疫 将检查对婴儿血友病中FVIII的反应 一个人可以预测哪些是耐受性的，哪些将形成抗体 注入FVIII。 启动根除治疗可能是有益的 抗FVIII抗体成为临床问题。 这 一项大型国际研究提出了可能性的可能性 当抑制剂滴度开始时，诱导是最成功的 很低。 对于那些在出现后宽容的患者 抑制剂，将确定是否是由于抗体消失引起的 和/或出现其他非抑制抗体。 这 先前已经报道了耐受患者中新抗体的存在 但是他们与宽容状态的关系尚未阐明。