Adaptive immunity regulates arteriovenous fistula remodeling

适应性免疫调节动静脉内瘘重塑

• 批准号: 10574913
• 负责人: Alan Dardik
• 金额: $ 77.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574913
• 关键词: Address; Affect; Age; Arteriovenous fistula; Biology; Blood Vessels; Blood flow; Cell physiology; Cells; Chronic Kidney Failure; Clinical; Clinical Trials; Cyclosporine; Data; Encapsulated; End stage renal failure; Environment; Expenditure; Failure; Female; Fistula; Gonadal Steroid Hormones; Healthcare; Hemodialysis; Hormones; Human; Hyperplasia; Immune; Immune response; Innate Immune Response; Intervention; Investigation; Knowledge; Legal patent; Macrophage; Mechanics; Mediating; Methodology; Modeling; Mus; Needles; Nephrectomy; Operative Surgical Procedures; Outcome; Patients; Persons; Physiology; Pregnancy; Procedures; Puncture procedure; Resources; Role; Sex Differences; Specimen; T cell therapy; T-Lymphocyte; Techniques; Testing; Thick; Vein graft; Veins; Venous; Woman; Work; adaptive immune response; adaptive immunity; clinical translation; experience; hemodynamics; human disease; improved; in vivo; in vivo Model; innovation; local drug delivery; male; men; mouse model; nanoparticle; next generation; novel; novel strategies; programmed cell death ligand 1; response; sexual dimorphism; shear stress; tool; transcriptomics

The preferred vascular access for hemodialysis to treat end-stage renal disease involves using a vein as a conduit to increase blood flow by surgically creating an arteriovenous fistula (AVF). Successful adaptation of a venous conduit to the fistula or arterial environment requires remodeling of the vein wall without excessive wall thickening, enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week. However, the poor maturation and patency of AVF, especially in women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the biology of venous remodeling that leads to successful venous adaptation to the fistula environment. This knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby to increase successful clinical use of venous conduits. Using a mouse AVF model that recapitulates human AVF maturation and shows sex differences, we have shown that both an innate immune response as well as an adaptive immune response regulate venous remodeling. We present exciting new data that sex hormones mediate sex differences in wall thickness during venous remodeling. In addition, we have developed the mouse model further to incorporate chronic kidney disease (CKD) via 5/6-nephrectomy; AVF in the CKD environment show altered venous remodeling compared with control mice and these AVF faithfully recapitulate human AVF maturation. We hypothesize that since T cells mediate venous remodeling, modulating adaptive immunity will alter venous remodeling, thereby improving AVF patency and ultimately fistula utilization in human patients. We will use our translationally relevant in vivo model, an innovative tool encapsulating cyclosporine in nanoparticles for local drug delivery, innovative methodology to analyze the immune cell composition within the AVF wall, as well as advanced next- generation analyses using transcriptomics techniques that are available at Yale, to test our innovative hypothesis with the following specific aims: Aim I: Determine whether sex differences in adaptive immunity between women and men affect AVF remodeling in vivo. Aim II: Determine whether sex hormones mediate sex differences in the immune response during AVF remodeling in mice with CKD. Aim III: Determine whether PD-L1 expression regulates the effects of adaptive immunity on AVF remodeling in mice with CKD. A successful outcome of this investigation will have lasting impact by establishing whether there is a T cell basis underlying venous remodeling and thus manipulation of adaptive immunity is a valuable strategy for clinical translation to enhance AVF patency. We will also determine whether reduced AVF maturation in women is due to sex differences in adaptive immunity. We use an innovative strategy and novel tools and models to manipulate adaptive immunity to alter venous remodeling and thereby improve AVF patency.

血液透析治疗终末期肾病的首选血管通路包括使用静脉 作为通过手术创建动静脉瘘（AVF）来增加血流的管道。成功的适应 静脉导管到瘘管或动脉环境的再成形需要静脉壁的再成形而不需要过度的 壁增厚，使机械强度能够抵抗刺穿AVF壁的血液透析手术 用大口径针头每周注射三次然而，AVF的成熟和通畅性差，特别是在 妇女和需要额外的重做程序和手术，反映了我们的不完善的理解， 静脉重塑的生物学，导致静脉成功适应瘘管环境。这 知识的差距造成了对新方法的未满足的需求，以增强静脉重塑，从而 增加静脉导管成功临床应用。 使用小鼠AVF模型，重现人类AVF成熟并显示性别差异，我们 已经表明，先天性免疫反应以及适应性免疫反应都调节静脉 重塑我们提出了令人兴奋的新数据，性激素介导的性别差异，在壁厚， 静脉重塑此外，我们还进一步开发了小鼠模型， 通过5/6肾切除术治疗慢性肾脏病（CKD）; CKD环境中的AVF显示静脉重塑改变， 这些AVF忠实地再现了人AVF的成熟。我们假设，由于T 细胞介导静脉重塑，调节适应性免疫将改变静脉重塑， 改善AVF通畅性并最终改善人类患者的瘘管利用率。我们将谨慎地使用 相关的体内模型，一种将环孢菌素包封在纳米颗粒中用于局部药物递送的创新工具， 创新的方法来分析AVF壁内的免疫细胞组成，以及先进的下一步- 使用耶鲁大学提供的转录组学技术进行世代分析，以测试我们的创新 假设，具体目标如下： 目的I：确定男女之间获得性免疫的性别差异是否影响AVF 体内重塑。目的II：确定性激素是否介导免疫反应的性别差异 在CKD小鼠的AVF重构中。目的III：确定PD-L1表达是否调节效应 获得性免疫对CKD小鼠AVF重构的影响。 这项调查的成功结果将通过确定是否存在T 静脉重塑的细胞基础，从而操纵适应性免疫是一种有价值的策略， 临床转化以增强AVF通畅性。我们还将确定是否减少AVF成熟， 女性是由于获得性免疫的性别差异。我们使用创新的战略和新的工具， 模型来操纵适应性免疫以改变静脉重塑，从而改善AVF通畅性。