Graft-targeted anti-complement therapy to reduce cardiac graft injury and allograft vasculopathy

摘要 在心脏移植(TX)的背景下，这是本申请的重点，原发性移植失败和 心脏移植物血管病变(AV)仍然是短期和长期存活的主要限制因素。课程， 自心脏TX手术开始以来，室性心动过速的严重性和发作几乎没有变化，尽管 T细胞免疫抑制。原发移植物衰竭和移植物衰竭发生的确切机制 慢性房室未被很好地了解，在这里，我们调查供体脑死亡(BD)诱导的损伤和 缺血再灌注损伤(IRI)在房室发育中的作用及补体在其中的作用。 脑死亡导致的损伤和IRI是大多数器官移植中不可避免的事件，它们是主要的 临床问题被认为对移植物的短期和长期存活都起着重要作用。天然 自身反应性IgM和补体在这两种类型的损伤中都起着主要作用，在这里我们研究了新的 移植物靶向IgM阻断和补体抑制作为急性给药的方法 心脏移植后免疫抑制剂，以确定移植后急性炎症和 损伤对慢性排斥反应的发生有调节作用。我们还将调查补充语和 移植物靶向的IgM和补体抑制策略影响心脏房室的发展 亚治疗T细胞免疫抑制疗法(雷帕霉素和他克莫司)，以及如何使用 补体抑制作为一种辅助治疗调节房室。通过将针对特定损伤后的部分连接起来- 在心脏(和其他器官/组织)移植物中表达的针对不同补体抑制剂的缺血新表位， 我们将能够研究补体如何调节急性损伤和随后的慢性排斥反应。我们 期望阐明参与房室发育的补体依赖机制，并确定一种 进一步开发的治疗候选药物将允许使用免疫保护免疫抑制药 治疗。

Abstract In the context of heart transplantation (Tx), which is the focus of this application, primary graft failure and cardiac allograft vasculopathy (AV) remain the major limitations to short and long-term survival. The course, severity and onset of AV have changed little since the inception of cardiac Tx surgery, despite improvements in T cell immunosuppression. The precise mechanisms involved in the development of primary graft failure and chronic AV are not well understood, here we investigate the role of donor brain death (BD)-induced injury and ischemia reperfusion injury (IRI) in the development of AV, and the role of complement in these processes. Brain death-induced injury and IRI are unavoidable events in most organ transplantations, and they are major clinical problems that are thought to play important roles in both short-term and long-term graft survival. Natural self-reactive IgM and complement play a major role in both types of injury, and here we investigate novel approaches of using graft-targeted IgM blockade and complement inhibition, administered as an acute immunosuppressant after cardiac transplantation, to determine how acute post-transplant inflammation and injury modulates the development of AV (chronic rejection). We will also investigate how complement and graft-targeted strategies of IgM and complement inhibition affect the development of cardiac AV in the context of subtherapeutic T cell immunosuppressive therapy (rapamycin and tacrolimus), and how the use of complement inhibition as an adjuvant therapy modulates AV. By linking moieties that target injury-specific post- ischemic neoepitopes expressed in cardiac (and other organ/tissue) grafts to different complement inhibitors, we will be able to investigate how complement modulates acute injury and subsequent chronic rejection. We expect to elucidate complement-dependent mechanisms involved in the development of AV, and to identify a therapeutic candidate for further development that will permit the use of immune-sparing immunosuppressive therapies.