Chronic Graft Destruction: Interplay of Allo- and Autoantibodies and Nonadherence
慢性移植物破坏:同种抗体和自身抗体的相互作用以及不依从
基本信息
- 批准号:8996113
- 负责人:
- 金额:$ 14.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-01 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:11 year old21 year oldAcuteAddressAdherenceAdverse eventAftercareAllograftingAngiographyAntibodiesAntibody FormationApoptoticAreaAutoantibodiesAutoantigensAutoimmunityAutomobile DrivingBlood capillariesBortezomibBrain natriuretic peptideCardiac MyosinsCell Culture TechniquesCellular StructuresCessation of lifeChildChildhoodChronicClinicalCohort StudiesComplementComplexComplicationCoronaryCoronary heart diseaseDevelopmentDonor SelectionEchocardiographyEndothelial CellsEvaluationEventFailureFunctional disorderHealthHeartHeart TransplantationHeart failureImage AnalysisImmunityImmunoglobulin GIncidenceInterventionIsoantibodiesLabelLaboratoriesLeadLiteratureMediatingMedicalModelingN-terminalOutcomePalliative CarePatientsPerioperativePharmaceutical PreparationsPhasePlayPopulationProductionProtocols documentationRandomized Controlled TrialsRecurrenceRegimenRisk FactorsRoleSafetySecondary toSerious Adverse EventSerumSignal TransductionStagingTechnologyTeenagersTransplantationVascular DiseasesVimentinadverse outcomebasecapillarycohortcytotoxicitydesensitizationfallsgraft functionhandheld mobile devicehazardheme oxygenase-1hemodynamicsimprovedinnovationinterstitialintervention effectisoimmunitymolecular pathologymortalitynovelopen labeloutcome forecastpalliativepreventprogenitorrandomized trialsenescencetreatment choice
项目摘要
DESCRIPTION (provided by applicant): Heart transplantation remains a palliative therapy with few recipients achieving survival beyond 20 years. Early results have improved secondary to reductions in perioperative mortality and early acute rejection rates have also fallen. However, ongoing graft loss occurs at a steady state of 2-3% per year after the first year with 'chronic rejection' being the commonest cause of late graft loss. Current medication regimens are effective at preventing acute rejection but appear to be largely ineffective at preventing graft vasculopathy. Our failure to make strides in this area reflects our ignorance of the mechanisms driving this serious complication. An emerging literature suggests that donor-specific HLA antibodies (DSA) are key drivers of chronic graft loss, and nonadherence may play an important role in their development. There is also a mounting body of literature to suggest that immunity to self-antigens plays an important role in the development of graft vasculopathy, though this has not been studied in children. We aim to address the complex interplay between alloimmunity, autoimmunity and nonadherence. We will address these themes through three interrelated studies. Project 1 is an observational cohort study to determine the long-term impact of DSA (preformed versus de novo) and antibodies to self-antigens (cardiac myosin, vimentin) on chronic graft function. We will also evaluate the impact of allo- and autoantibodies on the incidence of late (>1 year) serious adverse events including death, acute rejection, and acute graft dysfunction. Risk factors for outcomes will be defined, and the molecular pathology of late rejection episodes will be evaluated. The impact of antibodies on the development of altered microvascular pathophysiology will be assessed through evaluation of endothelial cell structure and signaling, interstitial capillary network and obliterative microvasculopathy (arteriolopathy). Innovative multiplex labeling, automated image analysis and endothelial cell culture models will be used to accomplish this endpoint. We hypothesize that de novo DSA will be the strongest predictors of adverse outcomes and development of microvasculopathy and that nonadherence will drive this complication. Project 2 will be a randomized, controlled trial of a novel mobile device application (Teen Pocket PATH) to improve adherence in children greater than 11 years of age after heart transplantation. We hypothesize that the intervention will improve adherence to medications and will reduce acute rejection events. We also hypothesize that this will lead to less de novo production of allo- and autoantibodies. Project 3 will be a phase II non-randomized, open label trial of a bortezomib-based regimen for desensitization of highly sensitized pediatric heart transplant candidates to assess the safety of the regimen in a pediatric population and to assess efficacy via evaluation of calculated PRA, antibody strength and complement fixing ability/IgG subclass and proportion of patients with negative cross-match against donor on pre- versus post-treatment sera. We hypothesize that a bortezomib-based regimen will be effective in reducing anti-HLA antibodies and reducing calculated PRA.
描述(由申请人提供):心脏移植仍然是一种姑息治疗,很少接受者能存活超过20年。早期结果得到改善,其次是围手术期死亡率的降低,早期急性排斥率也有所下降。然而,在第一年后,持续的移植物损失以每年2-3%的稳定状态发生,“慢性排斥”是晚期移植物损失的最常见原因。目前的药物治疗方案在预防急性排斥反应方面是有效的,但在预防移植物血管病变方面似乎大多无效。我们未能在这方面取得进展反映了我们对导致这一严重复杂情况的机制的无知。一项新的研究表明,供体特异性HLA抗体(DSA)是慢性移植物损失的关键驱动因素,而不粘连可能在其发展中起重要作用。也有越来越多的文献表明,对自身抗原的免疫在移植物血管病变的发展中起着重要作用,尽管尚未在儿童中进行研究。我们的目的是解决复杂的相互作用之间的异体免疫,自身免疫和不依从。我们将通过三个相互关联的研究来解决这些主题。项目1是一项观察性队列研究,旨在确定DSA(预成型vs新生)和自身抗原抗体(心肌蛋白、静脉蛋白)对慢性移植物功能的长期影响。我们还将评估同种异体抗体和自身抗体对晚期(10 ~ 10年)严重不良事件发生率的影响,包括死亡、急性排斥反应和急性移植物功能障碍。结果的危险因素将被定义,晚期排斥事件的分子病理学将被评估。抗体对微血管病理生理改变的影响将通过内皮细胞结构和信号、间质毛细血管网络和闭塞性微血管病变(动脉病变)的评估来评估。创新的多重标记、自动图像分析和内皮细胞培养模型将用于实现这一目标。我们假设从头DSA将是不良结果和微血管病变发展的最强预测因子,而不依从性将导致这种并发症。项目2将是一项随机对照试验,研究一种新型移动设备应用程序(Teen Pocket PATH),以提高11岁以上儿童心脏移植后的依从性。我们假设,干预将提高药物依从性,并将减少急性排斥事件。我们还假设,这将导致更少的新产生的异体抗体和自身抗体。项目3将是一项II期非随机、开放标签试验,以硼替佐米为基础的方案,用于高度敏感的儿童心脏移植候选人的脱敏,以评估该方案在儿科人群中的安全性,并通过评估计算的PRA、抗体强度和补体固定能力/IgG亚类以及治疗前后血清中与供体交叉配型阴性的患者比例来评估疗效。我们假设硼替佐米为基础的方案将有效减少抗hla抗体和减少计算PRA。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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STEVEN A. WEBBER其他文献
STEVEN A. WEBBER的其他文献
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{{ truncateString('STEVEN A. WEBBER', 18)}}的其他基金
Vanderbilt Stimulating Access to Research in Residency (V-StARR)
范德比尔特促进住院医师研究机会 (V-StARR)
- 批准号:
10591987 - 财政年份:2023
- 资助金额:
$ 14.64万 - 项目类别:
Chronic Graft Destruction: Interplay of Allo- and Autoantibodies and Nonadherence
慢性移植物破坏:同种抗体和自身抗体的相互作用以及不依从
- 批准号:
9590743 - 财政年份:2018
- 资助金额:
$ 14.64万 - 项目类别:
Vanderbilt Stimulating Access to Research in Residency (V-StARR)
范德比尔特促进住院医师研究机会 (V-StARR)
- 批准号:
10201735 - 财政年份:2018
- 资助金额:
$ 14.64万 - 项目类别:
Pathogenesis, Targeted Therapeutics, and New Vaccines for Childhood Disease
儿童疾病的发病机制、靶向治疗和新疫苗
- 批准号:
9217660 - 财政年份:2016
- 资助金额:
$ 14.64万 - 项目类别:
Pathogenesis, Targeted Therapeutics, and New Vaccines for Childhood Disease
儿童疾病的发病机制、靶向治疗和新疫苗
- 批准号:
10372216 - 财政年份:2016
- 资助金额:
$ 14.64万 - 项目类别:
Pathogenesis, Targeted Therapeutics, and New Vaccines for Childhood Disease
儿童疾病的发病机制、靶向治疗和新疫苗
- 批准号:
10225917 - 财政年份:2016
- 资助金额:
$ 14.64万 - 项目类别:
Chronic Graft Destruction: Interplay of Allo- and Autoantibodies and Nonadherence
慢性移植物破坏:同种抗体和自身抗体的相互作用以及不依从性
- 批准号:
8466120 - 财政年份:2013
- 资助金额:
$ 14.64万 - 项目类别:
Chronic Graft Destruction: Interplay of Allo- and Autoantibodies and Nonadherence
慢性移植物破坏:同种抗体和自身抗体的相互作用以及不依从
- 批准号:
8606403 - 财政年份:2013
- 资助金额:
$ 14.64万 - 项目类别:
Alloantibodies in Cardiac Transplantation - Intervention, Outcomes and Mechanisms
心脏移植中的同种抗体 - 干预、结果和机制
- 批准号:
8034232 - 财政年份:2008
- 资助金额:
$ 14.64万 - 项目类别:
Alloantibodies in Cardiac Transplantation - Intervention, Outcomes and Mechanisms
心脏移植中的同种抗体 - 干预、结果和机制
- 批准号:
7914250 - 财政年份:2008
- 资助金额:
$ 14.64万 - 项目类别:
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