Targeting factor B to prevent transplant rejection

 描述（由申请人提供）：缺血后再灌注（IR），这在器官移植过程中必然发生，激发免疫反应，导致移植物功能障碍。描述新的，有效的治疗方法，以防止IR损伤有可能改变临床实践和改善患者的健康器官移植后。本项目的目标是确定补体因子B（fB）在移植后损伤中的作用， 新的小鼠和人fB拮抗剂，并开始在动物模型中测试它们。长期目标是使用抑制剂来防止人类同种异体移植物损伤。我们结合已发表的和初步的数据表明：阻断供体器官中的补体激活可提高小鼠同种异体移植物的存活率;与正常心脏组织中的水平相比，心脏移植患者活检组织中fB基因表达增加，并与移植物排斥反应等级相关;在鼠心肌IR模型中，fB-/-小鼠的损伤显著减少; fB显著降低心脏移植物的存活率。 在接受心脏直视手术的患者的心脏中被激活，即，在这些患者中，活化的fB片段Bb的水平与手术后循环心肌肌钙蛋白I（心肌损伤的标志物）的增加相关。因此，fB在供体器官中的表达和活化在移植排斥中是重要的。具体目的是：1）利用噬菌体展示肽库鉴定对鼠和人fB特异的小肽拮抗剂。2)确定fB在小鼠移植排斥反应中的作用并测试fB抑制的功效。我们希望这些研究将确定新的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，以支持人体研究在体内阻断fB。

 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.