Complement driven innate and adaptive autoreactivity in lung transplantation

肺移植中补体驱动的先天性和适应性自身反应

• 批准号: 10363208
• 负责人: Carl Atkinson
• 金额: $ 44.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-03 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363208
• 关键词: Acute; Allogenic; Allografting; Animals; Annexin A4; Antibodies; Antibody Formation; Autoantibodies; Autoimmune; Autoimmunity; Binding; Bronchiolitis; Case-Control Studies; Cessation of life; Chronic; Clinical; Collagen; Complement; Complement Activation; Complement Inactivators; Data; Development; Elastin; Event; Exposure to; Extracellular Matrix; Functional disorder; Goals; Graft Rejection; Human; Immune; Immune response; Immunity; Immunodeficient Mouse; Immunoglobulin G; Immunoglobulin M; Immunologics; Impairment; Inflammation; Injury; Lead; Link; Lung; Lung Transplantation; Lung diseases; Mediating; Modeling; Mus; Organ; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Phenotype; Plasma; Play; Process; Proteins; Pulmonary Emphysema; Reperfusion Injury; Reperfusion Therapy; Role; Sampling; Serum; Severities; Solid; Stress; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Tissue Transplantation; Transplant Recipients; Transplantation; X-Ray Computed Tomography; aged; alpha Tubulin; autoreactive T cell; autoreactivity; cell injury; cigarette smoke; cigarette smoke-induced; clinically relevant; cohort; complement system; decorin; early onset; effector T cell; exposure to cigarette smoke; improved; inhibitor/antagonist; lung allograft; lung injury; mouse model; neoantigens; novel; post-transplant; reconstitution; response; targeted treatment; transplant model

Abstract: Obliterative bronchiolitis (OB) is the leading cause of late death after lung transplantation (LTx) and the principle unmet obstacle to improved long-term outcomes. Increasing evidence indicates a role for recipient autoimmunity in the pathogenesis of graft rejection. Emphysema, a principle indication for LTx, has been shown to express a wide-spectrum of extracellular matrix autoreactive antibodies and T cells directed towards collagen, elastin, and decorin, the impact of which on post-Tx outcomes is unknown. Here we will utilize mouse models of emphysema, and orthopic LTx, to investigate LTx outcomes in a clinically relevant scenario. The scientific premise of these studies is to determine if pre-transplant autoreactive immunity induced by emphysema, promotes post-Tx injury that leads to exacerbated ischemia reperfusion injury (IRI) and OB. The earliest injury to the LTx occurs as a consequence of IRI, the severity of which is thought to lead to accelerated onset OB. Ischemic insult followed by reperfusion leads to the exposure of neoepitopes expressed on stressed/injured cells recognized by natural self-reactive IgM Abs, which bind and activate the C system, resulting in inflammation and injury. We have identified annexin IV as an injury-specific neoepitope expressed in ischemic transplant grafts, and have shown that this neoepitope binds natural IgM, activates C and promotes IRI. By means of an anti-annexin IV single chain Ab (B4scFv), we have validated annexin IV as a target for the therapeutic delivery of C inhibition to murine allografts. There are a number of therapeutic benefits of this neoepitope targeting approach for protection against IRI in a LTx recipient: 1. It will target the proximal event in complement activation, 2. The targeting vehicle itself contributes to therapeutic activity by blocking the binding of complement activating antibodies, and 3. Will inhibit C activation locally, which will impair T cell activation. Our working hypothesis is that pre-transplant autoreactivity to extracellular matrix targets exacerbates early graft injury, thus promoting early onset OB. We propose that neoepitope IgM graft-targeted C inhibitors will synergize to inhibit adaptive autoantibody effector functions, and reduce intragraft autoreactive T cell activity. We propose the following specific, independent, but interrelated aims. 1. Determine the complement-mediated effector functions that contribute to extracellular matrix autoreactive immunity induced acute lung graft injury. Here we will determine the isotype and phenotype of autoreactive antibodies and T cells that promote injury post transplantation and further dissect the complement effector functions that induce graft damage, and 2. In a murine model of OB, determine whether cigarette smoke-induced autoimmunity exacerbates IRI and chronic rejection following transplantation in a complement-dependent manner. We will transplant lungs into emphysematous mice (induced by cigarette smoke exposure) using allogeneic models of OB and determine whether prolonged CS exposure results in poorer outcomes, and further investigate how C-mediated inflammation and injury occurring early in the Tx process influences IRI and OB. !

【摘要】：闭塞性细支气管炎(OB)是肺移植(LTx)术后晚期死亡的主要原因。 改善长期成果的主要未解决障碍。越来越多的证据表明接受者的作用 自身免疫在移植排斥的发病机制中。肺气肿是 LTx 的一个主要适应症， 显示出表达广泛的细胞外基质自身反应抗体和 T 细胞 胶原蛋白、弹性蛋白和核心蛋白聚糖，它们对 Tx 后结果的影响尚不清楚。这里我们将使用鼠标 肺气肿和矫形 LTx 模型，以研究临床相关场景中的 LTx 结果。这 这些研究的科学前提是确定移植前自身反应性免疫是否由 肺气肿，促进 Tx 后损伤，导致缺血再灌注损伤 (IRI) 和 OB 加剧。 LTx 最早的损伤是 IRI 的结果，其严重程度被认为会导致 加速发作 OB。缺血性损伤随后再灌注导致表达的新表位暴露 作用于被天然自身反应性 IgM 抗体识别的应激/受伤细胞，该抗体结合并激活 C 系统， 从而导致炎症和损伤。我们已经确定膜联蛋白 IV 是一种表达的损伤特异性新表位 在缺血性移植物中，并表明该新表位结合天然 IgM，激活 C 并促进 IRI。通过抗膜联蛋白 IV 单链抗体 (B4scFv)，我们已验证膜联蛋白 IV 作为 对小鼠同种异体移植物进行 C 抑制的治疗性递送。这种疗法有很多治疗益处 用于保护 LTx 接受者免受 IRI 的新表位靶向方法： 1. 它将针对近期事件 补体激活，2.靶向载体本身通过阻断结合来促进治疗活性 补体激活抗体，以及 3. 将局部抑制 C 激活，这将损害 T 细胞激活。 我们的工作假设是，移植前对细胞外基质靶标的自身反应性会在早期加剧 移植物损伤，从而促进早发OB。我们建议新表位 IgM 移植物靶向 C 抑制剂将 协同抑制适应性自身抗体效应功能，并降低移植物内自身反应性 T 细胞活性。 我们提出以下具体、独立但相互关联的目标。 1. 确定补体介导的 有助于细胞外基质自身反应性免疫诱导急性肺移植损伤的效应器功能。 在这里，我们将确定促进损伤的自身反应性抗体和 T 细胞的同种型和表型 移植后并进一步剖析诱导移植物损伤的补体效应器功能，以及 2. 在 OB 小鼠模型，确定香烟烟雾诱导的自身免疫是否会加剧 IRI 和慢性 以补体依赖性方式进行移植后的排斥反应。我们将把肺移植到 使用同种异体 OB 模型对肺气肿小鼠（由香烟烟雾暴露诱发）进行测定 长期接触CS是否会导致较差的结果，并进一步研究C如何介导 Tx 过程早期发生的炎症和损伤会影响 IRI 和 OB。 ！

项目成果

MicroRNA-206 antagomiR‒enriched extracellular vesicles attenuate lung ischemia‒reperfusion injury through CXCL1 regulation in alveolar epithelial cells.

MicroRNA-206 antagomir 富集的细胞外囊泡通过肺泡上皮细胞中的 CXCL1 调节减轻肺缺血再灌注损伤。

• 发表时间: 2020
• 作者: Cai, Jun;Gehrau, Ricardo;Tu, Zhenxiao;Leroy, Victoria;Su, Gang;Shang, Junyi;Mas, Valeria R;Emtiazjoo, Amir;Pelaez, Andres;Atkinson, Carl;Machuca, Tiago;Upchurch Jr, Gilbert R;Sharma, Ashish K
• 通讯作者: Sharma, Ashish K

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2021.

机器灌注器官保存：2021 年美国移植大会的亮点。

• 发表时间: 2022-02
• 影响因子: 2.4
• 作者: Pavan;Zarrinpar, Ali;Beduschi, Thiago;Atkinson, Carl;Martins, Paulo N
• 通讯作者: Martins, Paulo N

Resolution of post-lung transplant ischemia-reperfusion injury is modulated via Resolvin D1-FPR2 and Maresin 1-LGR6 signaling.

肺移植后缺血再灌注损伤的缓解通过 Resolvin D1-FPR2 和 Maresin 1-LGR6 信号传导进行调节。

• DOI: 10.1016/j.healun.2022.12.013
• 发表时间: 2022-12-01
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: V. Leroy;Jiong Cai;Z. Tu;A. McQuiston;Simrun Sharma;A. Emtiazjoo;C. Atkinson;Gilbert R. Upchurch;Ashish K. Sharma
• 通讯作者: Ashish K. Sharma

Nanotherapeutics in transplantation: How do we get to clinical implementation?

移植中的纳米治疗：我们如何进行临床实施？

• DOI: 10.1111/ajt.17012
• 发表时间: 2022-05
• 期刊: American Journal of Transplantation
• 影响因子: 8.8
• 作者: Plumblee, Leah;Atkinson, Carl;Jaishankar, Dinesh;Scott, Evan;Tietjen, Gregory T.;Nadig, Satish N.
• 通讯作者: Nadig, Satish N.