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: 10228849
• 负责人: Carl Atkinson
• 金额: $ 14.49万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228849
• 关键词: Acute; Allogenic; Allografting; Animals; Annexin A4; Antibodies; Antibody Formation; Autoantibodies; Autoimmune Process; 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：闭塞性支气管炎（OB）是肺移植后晚期死亡的主要原因（LTX）和 改善长期结局的原则未满足的障碍。越来越多的证据表明接受者的作用 移植排斥的发病机理中的自身免疫性。肺气肿是LTX的原理指示，已经是 显示出表达广泛的细胞外基质自动反应性抗体和T细胞针对的T细胞 胶原蛋白，弹性蛋白和Decorin，其对TX后结果的影响尚不清楚。在这里，我们将使用鼠标 在临床相关的情况下，肺气肿模型和原始LTX模型研究LTX结果。这 这些研究的科学前提是确定移植前自动反应性免疫是否由 肺气肿，促进TX后损伤，导致加剧的缺血再灌注损伤（IRI）和OB。 IRI的结果是最早的LTX伤害，其严重程度被认为导致 加速发作OB。缺血性侮辱，然后再灌注会导致表达的新皮标暴露 在由自然自反应性IgM ABS识别的压力/受伤细胞上，该ABS结合并激活C系统， 导致炎症和伤害。我们已经将膜联蛋白IV确定为表达的特定损伤的新皮子 在缺血性移植移植物中，已经表明该新皮子结合天然IgM，激活C并促进 艾里。通过抗动脉毒素IV单链AB（B4SCFV），我们已验证了膜联蛋白IV作为目标 C抑制对鼠同种异体移植的治疗递送。这有很多治疗好处 LTX收件人中的NEOEPITOPE靶向方法：1。它将针对近端事件 补体激活，2。靶向车辆本身通过阻断结合来有助于治疗活动 补体激活抗体，3。将局部抑制C激活，这会损害T细胞的激活。 我们的工作假设是，对细胞外基质靶标的移植前自动反应早期加剧 移植损伤，从而促进早期发作OB。我们提出，新皮子IGM靶向靶向C抑制剂将 协同抑制适应性自身抗体效应子功能，并减少自动反应性T细胞活性。 我们提出以下特定，独立但相互关联的目标。 1。确定补体介导的 效应子功能有助于细胞外基质自动反应性免疫引起急性肺移植损伤。 在这里，我们将确定促进损伤的自动反应性抗体和T细胞的同型和表型 移植后并进一步剖析诱导移植损伤的补体效应子功能，其中2。 OB的鼠模型，确定香烟烟雾引起的自身免疫性是否加剧了IRI和慢性 以补体依赖性方式移植后的拒绝。我们将肺部移植到 使用OB的同种异体模型并确定的杂质小鼠（通过香烟烟雾诱导） 长时间的CS暴露是否导致结果较差，并进一步研究C介导的 在TX过程的早期发生炎症和伤害会影响IRI和OB。 呢