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

摘要 在作为本申请的焦点的心脏移植（Tx）的背景下，原发性移植物衰竭和 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。课程， 自心脏Tx手术开始以来，AV的严重程度和发作几乎没有变化，尽管在 T细胞免疫抑制。原发性移植物衰竭发生的确切机制， 慢性AV还没有得到很好的理解，在这里，我们研究供体脑死亡（BD）诱导的损伤和 缺血再灌注损伤（IRI）在AV发展中的作用，以及补体在这些过程中的作用。 脑死亡引起的损伤和IRI是大多数器官移植中不可避免的事件， 被认为在短期和长期移植物存活中起重要作用的临床问题。自然 自身反应性IgM和补体在这两种类型的损伤中起主要作用，在这里，我们研究了新的 使用移植物靶向的IgM阻断和补体抑制的方法，作为急性给药， 免疫抑制剂，以确定如何急性移植后炎症和 损伤调节AV（慢性排斥）的发展。我们还将研究如何补充和 IgM和补体抑制的移植物靶向策略影响心脏AV的发展 亚治疗性T细胞免疫抑制治疗（雷帕霉素和他克莫司），以及如何使用 补体抑制作为辅助疗法调节AV。通过连接靶向损伤特异性后- 在心脏（和其他器官/组织）移植物中表达的缺血性新表位对不同的补体抑制剂， 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。我们 希望阐明补体依赖性机制参与AV的发展，并确定一个 用于进一步开发的治疗候选物，其将允许使用免疫保留的免疫抑制剂， 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.