Targeting factor B to prevent transplant rejection

 描述(由申请人提供)：在器官移植过程中不可避免地发生缺血和再灌注(IR)，引起免疫反应，从而导致移植物功能障碍。寻找新的、有效的治疗方法来预防IR损伤，有可能改变临床实践，改善器官移植后患者的健康。该项目的目标是确定补体因子B(FB)在移植后损伤中的作用，确定 新的小鼠和人类FB拮抗剂，并开始在动物模型中测试它们。长期目标是使用这些抑制剂来预防人类同种异体移植物的损伤。我们联合发表的和初步的数据表明：阻断供者器官中的补体激活可以延长小鼠同种异体移植物的存活时间；与正常心脏组织相比，心脏移植患者的活检组织中Fb基因的表达增加，并与移植排斥反应分级相关；在小鼠心肌IR模型中，Fb-/-小鼠的损伤显著减轻；Fb显著 在这些患者中，激活的FB片段的水平与手术后循环中心肌肌钙蛋白I的升高有关，而循环心肌肌钙蛋白I是心肌损伤的标志。因此，FB在供体器官中的表达和激活在移植物排斥反应中起着重要作用。其具体目的是：1)利用噬菌体展示多肽文库鉴定小鼠和人FB特异性的小肽拮抗剂。2)确定Fb在小鼠移植排斥反应中的作用，并检测Fb的抑制作用。我们期望这些研究将发现新的FB抑制剂，为IR损伤和移植排斥反应的机制提供新的见解，并提供临床前数据支持体内阻断FB的人类研究。

 DESCRIPTION (provided by applicant): Ischemia followed by reperfusion (IR), which occurs unavoidably during organ transplantation, elicits immune responses that contribute to graft dysfunction. Delineating novel, effective therapies to prevent IR injury has the potential to change clinical practice and improve patient health following organ transplantation. The goals of this project are to define the role of complement factor B (fB) in post-transplant injury, identify new mouse and human fB antagonists and begin to test them in animal models. The long term goal is to use the inhibitors to prevent allograft injury in humans. Our combined published and preliminary data demonstrate that: blocking complement activation in a donor organ prolongs allograft survival in mice; fB gene expression is increased in biopsies of heart transplantation patients compared with levels in normal heart tissue, and correlates with graft rejection grades; in a murine myocardial IR model, injury is significantly reduced in fB-/- mice; fB is significantly activated in the hearts of patients undergoing open heart surgery, i.e., experiencing surgically-induced global heart ischemia; in these patients, the levels of Bb, the activated fB fragment, correlate with the post- surgical increase of circulating cardiac troponin I, a marker of myocardia injury. Thus, fB expression and activation in donor organs are important in graft rejection. The specific aims are: 1) To identify small peptide antagonists specific for murine and for human fB using a phage display peptide library. 2) To determine the role of fB in transplant rejection in mice and to test the efficacy of fB inhibition. We expect that the studies will identify novel fB inhibitors, provide new insight into mechanisms of IR injury and transplant rejection, and provide preclinical data to support human studies to block fB in vivo.