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

移植物靶向抗补体治疗可减少心脏移植物损伤和同种异体移植血管病变

基本信息

批准号：
10187511
负责人：
Carl Atkinson
金额：
$ 37.38万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187511
关键词：
Acute Adjuvant Therapy Affect Alloantigen Allografting Annexin A4 Area Binding Biological Availability Brain Death Brain Ischemia Cardiac Cardiac development Cell Communication Chemosensitization Chronic Clinical Complement Complement 3d Receptors Complement Activation Complement Inactivators Data Development Dose Encapsulated Endothelium Event Functional disorder Goals Graft Rejection Graft Survival Heart Transplantation Host Defense Human Immune Immunocompromised Host Immunoglobulin M Immunologic Factors Immunosuppression Immunosuppressive Agents Incidence Inflammation Inflammatory Inflammatory Response Injury Investigation Lectin Link Mediating Modeling Molecular Mus Myocardial Ischemia Operative Surgical Procedures Opsonin Organ Organ Transplantation Outcome Pathogenesis Pathogenicity Pathway interactions Pattern Pattern recognition receptor Pharmacology Phenotype Play Process Reperfusion Injury Reperfusion Therapy Risk Factors Role Severities Shapes Sirolimus Site Stress System T-Lymphocyte Tacrolimus Therapeutic Therapeutic Intervention Therapeutic immunosuppression Tissue Grafts Transplantation Vascular Diseases activation product adaptive immune response base cell injury clinically relevant complement pathway complement system graft failure heart allograft immunoregulation improved inhibitor/antagonist isoimmunity neoantigens novel strategies post-transplant receptor response targeted delivery targeted treatment therapeutic candidate tissue injury

项目摘要

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.

抽象的在心脏移植 (Tx) 的背景下，这是本应用的重点，原发性移植物衰竭和心脏同种异体移植血管病（AV）仍然是短期和长期生存的主要限制。课程，自心脏 Tx 手术开始以来，尽管 AV 的严重程度和发病率有所改善，但 AV 的严重程度和发病率几乎没有变化。 T细胞免疫抑制。原发性移植物衰竭发生的精确机制和慢性 AV 尚不清楚，在这里我们研究供体脑死亡 (BD) 引起的损伤和 AV 发展中的缺血再灌注损伤 (IRI)，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，也是主要的事件。被认为在短期和长期移植物存活中发挥重要作用的临床问题。自然的自身反应性 IgM 和补体在这两种类型的损伤中都发挥着重要作用，在这里我们研究了新的使用移植物靶向 IgM 阻断和补体抑制的方法，作为急性给药心脏移植后免疫抑制剂，以确定移植后急性炎症和损伤会调节 AV（慢性排斥反应）的发展。我们还将研究如何补充和 IgM 和补体抑制的移植靶向策略影响心脏 AV 的发展亚治疗 T 细胞免疫抑制疗法（雷帕霉素和他克莫司）的作用，以及如何使用补体抑制作为辅助治疗调节 AV。通过连接针对特定损伤后的部分心脏（和其他器官/组织）移植物中表达的缺血新表位针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反应。我们希望阐明 AV 发展中涉及的补体依赖性机制，并确定一个进一步开发的治疗候选药物将允许使用免疫保留免疫抑制剂疗法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation.

新型 P-选择素靶向补体抑制剂在小鼠后肢损伤和移植模型中的表征。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Zheng, Chaowen;Ricci, Jerec;Zhang, Qinqin;Alawieh, Ali;Yang, Xiaofeng;Nadig, Satish;He, Songqing;Engel, Pablo;Jin, Junfei;Atkinson, Carl;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen

Increasing the efficacy and safety of a human complement inhibitor for treating post-transplant cardiac ischemia reperfusion injury by targeting to a graft-specific neoepitope.

通过靶向移植物特异性新表位，提高人类补体抑制剂治疗移植后心脏缺血再灌注损伤的功效和安全性。

DOI：
发表时间：
2021-10
期刊：
影响因子：
0
作者：
Zheng, Chaowen;Sleiman, Mohamad Mahdi;Yang, Xiaofeng;He, Songqing;Atkinson, Carl;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen

Surgical Innovation: Heart Transplantation After Cardiac Death.

外科创新：心脏死亡后的心脏移植。

DOI：
发表时间：
2021-10
期刊：
影响因子：
1.5
作者：
Rajab, Taufiek Konrad;Chen, Sarah;Nadig, Satish N;Atkinson, Carl
通讯作者：
Atkinson, Carl

Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling.

补体抑制通过调节磷酸肌醇 3-激酶信号传导减轻供体脑死亡引起的肝损伤和移植后级联损伤。

DOI：
发表时间：
2023-04
期刊：
影响因子：
0
作者：
Lin, Chengjie;Lei, Biao;Dong, Chunqiang;Chen, Junze;Chen, Shilian;Jiang, Keqing;Zeng, Yonglian;Su, Huizhao;Jin, Hu;Qiu, Xiaoqiang;Li, Zeyuan;Hu, Zhigao;Yu, Shuiping;Zhang, Cheng;Lu, Shiliu;Atkinson, Carl;Tomlinson, Stephen;Zhong, Fudi;Yu
通讯作者：
Yu

Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease.

靶向补体替代途径可实现移植物抗白血病活性，同时预防移植物抗宿主病。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Nguyen, Hung;Alawieh, Ali;Bastian, David;Kuril, Sandeepkumar;Dai, Min;Daenthanasanmak, Anusara;Zhang, Mengmeng;Iamsawat, Supinya;Schutt, Steven D;Wu, Yongxia;Sleiman, M Mahdi;Shetty, Akshay;Atkinson, Carl;Sun, Shaoli;Varela, Juan Carlos;Tom
通讯作者：
Tom