Immunobiology of GPIIb/IIIa

GPIIb/IIIa 的免疫生物学

• 批准号: 6589308
• 负责人: Richard Herbert Aster
• 金额: $ 27.32万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589308
• 关键词: anticoagulants; autoantibody; binding sites; blood transfusion; clinical research; drug adverse effect; fibrinogen receptors; human subject; immunoglobulin genes; immunoglobulins; integrins; laboratory mouse; monoclonal antibody; platelet activation; receptor binding; thrombocytopenia; vascular endothelium

Fibrinogen receptor antagonists (FRAs) are a promising new family of anti-thrombotic drugs. However, in clinical trial of these agents conducted to date, 0.1-1.0% of treated patients has experienced acute, severe thrombocytopenia. Although clinical presentation suggests an immunologic etiology, very little published information on this point is available. In preliminary studies, we have obtained evidence that FRA- induced thrombocytopenia is caused by antibodies (abs), often "naturally occurring", that recognize GPIIb/IIIa on platelets treated with an FRA. In this application, we propose studies to characterize the pathogenesis of this disorder, explore the significance of the responsible "natural" antibodies, and develop improved methods for diagnosis and for identifying patients at risk to develop this complication. Pathogenesis-Abs associated with FRA-induced thrombocytopenia will be characterized with emphasis on the following hypotheses: 1) Abs that cause thrombocytopenia in patients treated with abciximab (ReoPro) are specific for C terminal (human) peptide sequences and/or murine sequences in the chimeric abciximab molecule and 2) Abs in patients treated with ligand-mimetic compounds recognized ligand-binding sites (LIBS) on BPII/IIIA. We will seek to develop a murine model of thrombocytopenia induced by ligand-mimetic FRAs in which mechanisms of FRA-induced thrombocytopenia and the origin of the responsible abs can be systematically studied. Information gained will be used to develop sensitive, specific and practical methods for identifying abs capable of causing thrombocytopenia in FRA-treated patients and for predicting whether an FRA can be safely administered. "Natural Antibodies" (NA)-NA have been implicated in normal body homeostasis and in various immune disorders. We propose to explore the hypothesis that some relative common NA recognize ligand-induced conformation changes in the GPIIb/IIIa heterodimer, to characterize the relationship of these NA to FRA-induced thrombocytopenia, and to define their immunologic origin, their potential role in platelet and their effects on the quality of platelets stored prior to transfusion. B cell repertoire- We will utilize immunoglobin V gene amplification and phage display technology to define the B cell repertoire utilized by patients and normal subjects to generate abs specific for ligand-occupied GPIIb/IIIa and to characterize the relationship between NA and pathologic antibodies at a molecular level.

纤维蛋白原受体拮抗剂（FRAS）是一个有前途的抗血栓形成药物。但是，在迄今为止对这些药物进行的临床试验中，有0.1-1.0％的治疗患者经历了严重的严重血小板减少症。尽管临床表现提出了免疫学病因，但有关这一点的发表信息很少。在初步研究中，我们获得了证据表明，诱导的血小板减少症是由抗体（ABS）引起的，通常是“天然发生的”，这些抗体识别使用FRA治疗的血小板上的GPIIB/IIIA。在此应用中，我们建议研究以表征该疾病的发病机理，探索负责任的“自然”抗体的重要性，并开发改进的诊断方法，并确定有风险的患者发展这种并发症。 Pathogenesis-Abs associated with FRA-induced thrombocytopenia will be characterized with emphasis on the following hypotheses: 1) Abs that cause thrombocytopenia in patients treated with abciximab (ReoPro) are specific for C terminal (human) peptide sequences and/or murine sequences in the chimeric abciximab molecule and 2) Abs in patients treated with ligand-mimetic compounds BPII/IIIA上公认的配体结合位点（LIB）。我们将寻求开发由配体模拟FRA诱导的血小板减少症的鼠模型，其中可以系统地研究FRA诱导的血小板减少症的机制和负责任的ABS的起源。获得的信息将用于开发敏感，特定和实用的方法，用于识别能够在FRA治疗的患者中引起血小板减少症的ABS，并预测是否可以安全地施用FRA。 “天然抗体”（Na）-NA已与正常体内平衡和各种免疫疾病有关。我们建议探索以下假设：某些相对常见的NA识别GPIIB/IIIA异二聚体中配体诱导的构象变化，以表征这些NA与FRA诱导的血小板细胞减少症的关系，并定义其免疫原性，它们在血小板中的潜在作用及其对固定在平稳型质量的质量的影响。 B细胞曲目 - 我们将利用免疫白蛋白V基因扩增和噬菌体显示技术来定义患者和正常受试者使用的B细胞库，以产生特异性的ABS，特异性的GPIIB/IIIA并表征Naologic抗体与分子水平的病理性抗体之间的关系。