Reperfusion Injury Therapy: Role for IgM Antibody

描述(申请人提供)：缺血和再灌注是导致人类疾病的主要机制之一。当动脉或含氧血液供应中断到器官或组织时，就会发生缺血。再灌注指的是在缺血期后血流量的重建。对啮齿动物和大型动物的研究表明，补体系统是心肌、中枢神经系统、肠道和后肢等组织中缺血再灌注损伤的主要介质。我们最近的结果证实，天然的IgM抗体是补体依赖损伤的初始步骤。这一第一阶段的应用提出了两个具体目标：(1)确定鉴定分泌致病IgM的特定B-1细胞杂交瘤的可行性；(2)检查鉴定与启动损伤的特定IgM抗体结合的多肽的可行性。第一阶段的成功完成将导致第二阶段，这将测试概念证明，突变的IgM(不结合补体)和/或结合IgM的多肽将在体内阻止再灌注损伤。再灌注损伤是心脏病发作或冠状动脉事件、中风和创伤后的一种有文献记载的主要损伤机制，估计每年影响1300多万患者，市场价值35亿美元。目前，对于阻滞性损伤还没有有效的治疗方法。在炎症的最早阶段开发一种特异性的再灌注损伤抑制剂将提供重要的医学益处。考虑到受再灌注损伤影响的多种组织类型，确定在损伤诱导阶段起作用的抑制剂/S将具有广泛的商业应用。分泌启动损伤的抗体或内源性IgM的特异性抑制物的杂交瘤克隆的鉴定将为未来治疗的发展提供重要的基础。

DESCRIPTION (provided by applicant): Ischemia and reperfusion is one of the major mechanisms underlying human disease. Ischemia occurs when the arterial or oxygenated blood supply is interrupted to an organ or tissue. Reperfusion refers to the reestablishment of blood flow after the period of ischemia. Studies in rodents and large animals demonstrate that the complement system is a major mediator of ischemia-reperfusion injury in various tissues including myocardium, central nervous system, intestine and hindlimb. Our recent results identified natural IgM antibody as the initial step in complement-dependent injury. This phase I application proposes two specific aims: (1) determine the feasibility of identification of specific B-1 cell hybridomas that secrete pathogenic IgM; (2) examine the feasibility of identifying peptides that bind to the specific IgM antibodies that initiate injury. Successful completion of phase I will lead to phase II which will test the proof-of-concept that mutant IgM (does not bind complement) and/or peptides that bind IgM will block reperfusion injury in vivo. Reperfusion injury is a documented major mechanism of injury following heart attack or coronary events, stroke and trauma estimated to affect over 13 million patients per year and representing a $ 3.5 billion market. Currently, there are no effective treatments for blocking injury. Development of a specific inhibitor of reperfusion injury at the earliest stage of inflammation would provide an important medical benefit. The identification of an inhibitor/s that act at the induction stage of injury would have broad commercial application given the many types of tissues affected by reperfusion injury. The identification of hybridoma clones, which secrete antibody that initiates injury, or specific inhibitors of endogenous IgM will provide an important basis for development of future therapie.