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
基本信息
- 批准号:10228849
- 负责人:
- 金额:$ 14.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAllogenicAllograftingAnimalsAnnexin A4AntibodiesAntibody FormationAutoantibodiesAutoimmune ProcessAutoimmunityBindingBronchiolitisCase-Control StudiesCessation of lifeChronicClinicalCollagenComplementComplement ActivationComplement InactivatorsDataDevelopmentElastinEventExposure toExtracellular MatrixFunctional disorderGoalsGraft RejectionHumanImmuneImmune responseImmunityImmunodeficient MouseImmunoglobulin GImmunoglobulin MImmunologicsImpairmentInflammationInjuryLeadLinkLungLung TransplantationLung diseasesMediatingModelingMusOrganOutcomePathogenesisPathogenicityPathologicPatientsPhenotypePlasmaPlayProcessProteinsPulmonary EmphysemaReperfusion InjuryReperfusion TherapyRoleSamplingSerumSeveritiesSolidStressT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTimeTissue TransplantationTransplant RecipientsTransplantationX-Ray Computed Tomographyagedalpha Tubulinautoreactive T cellautoreactivitycell injurycigarette smokecigarette smoke-inducedclinically relevantcohortcomplement systemdecorinearly onseteffector T cellexposure to cigarette smokeimprovedinhibitor/antagonistlung allograftlung injurymouse modelneoantigensnovelpost-transplantreconstitutionresponsetargeted treatmenttransplant model
项目摘要
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)后晚期死亡的主要原因,
改善长期成果的主要障碍。越来越多的证据表明,
自身免疫在移植排斥发病机制中的作用。肺气肿是LTx的主要适应症,
显示出表达广谱的细胞外基质自身反应性抗体和T细胞,
胶原蛋白、弹性蛋白和核心蛋白聚糖,其对Tx后结果的影响尚不清楚。在这里,我们将使用鼠标
肺气肿和原位LTx模型,以研究临床相关场景中的LTx结局。的
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,导致加重的缺血再灌注损伤(IRI)和OB。
LTx的最早损伤是IRI的结果,其严重程度被认为会导致
加速发作OB。缺血损伤后再灌注导致表达的新表位暴露
对应激/损伤细胞的天然自身反应性IgM抗体识别,其结合并激活C系统,
导致炎症和损伤。我们已经确定膜联蛋白IV是一种损伤特异性新表位,
在缺血性移植物中,并且已经表明这种新表位结合天然IgM,激活C并促进
IRI。通过抗膜联蛋白IV单链抗体(B4scFv),我们已经验证了膜联蛋白IV作为靶点,
C抑制向鼠同种异体移植物的治疗性递送。这有很多治疗上的好处
用于在LTx接受者中保护免受IRI的新表位靶向方法:1.它将瞄准近端事件,
补体激活,2.靶向载体本身通过阻断结合而有助于治疗活性。
补体激活抗体,和3.会抑制局部的C活化,这会损害T细胞活化。
我们的工作假设是,移植前对细胞外基质靶点的自身反应性在早期恶化,
移植物损伤,从而促进早发性OB。我们提出,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子功能,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
影响细胞外基质自身反应性免疫诱导的急性肺移植物损伤的效应子功能。
在这里,我们将确定同种型和表型的自身反应性抗体和T细胞,促进损伤
移植后并进一步剖析诱导移植物损伤的补体效应子功能,和2.在
小鼠OB模型,确定香烟烟雾诱导的自身免疫是否加重IRI和慢性炎症。
以补体依赖性方式移植后的排斥反应。我们将把肺移植到
肺气肿小鼠(由香烟烟雾暴露诱导)使用同种异体OB模型,并确定
长期暴露于CS是否会导致不良结局,并进一步研究C介导的
在Tx过程早期发生的炎症和损伤影响IRI和OB。
!
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carl Atkinson其他文献
Carl Atkinson的其他文献
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{{ truncateString('Carl Atkinson', 18)}}的其他基金
Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation
将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应
- 批准号:
10481101 - 财政年份:2022
- 资助金额:
$ 14.49万 - 项目类别:
Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation
将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应
- 批准号:
10693272 - 财政年份:2022
- 资助金额:
$ 14.49万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 14.49万 - 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
- 批准号:
9886648 - 财政年份:2020
- 资助金额:
$ 14.49万 - 项目类别:
Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery
脑死亡相关血管化复合同种异体移植物损伤及其对同种免疫和功能恢复的影响
- 批准号:
10293947 - 财政年份:2020
- 资助金额:
$ 14.49万 - 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
- 批准号:
10355859 - 财政年份:2020
- 资助金额:
$ 14.49万 - 项目类别:
Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery
脑死亡相关血管化复合同种异体移植物损伤及其对同种免疫和功能恢复的影响
- 批准号:
10399007 - 财政年份:2020
- 资助金额:
$ 14.49万 - 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
- 批准号:
10094187 - 财政年份:2020
- 资助金额:
$ 14.49万 - 项目类别:
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