Adaptive immunity regulates arteriovenous fistula remodeling

血液透析治疗终末期肾病的首选血管通路包括使用静脉。 作为通过外科手术制造动静脉瘘(AVF)来增加血流量的管道。成功的适应 静脉导管通向瘘管或动脉环境需要重建静脉壁而不过度。 壁加厚，使机械强度能够抵抗穿透AVF壁的血液透析程序 使用大口径针头，每周3次。然而，动静脉瘘的成熟度和通畅性较差，特别是在 女性和需要额外的重做程序和手术，反映了我们对 静脉重塑的生物学，导致静脉成功适应瘘管环境。这 知识鸿沟创造了对增强静脉重塑的新方法的未得到满足的需求，从而 提高静脉导管的临床使用成功率。 利用重现人类动静脉瘘成熟并显示性别差异的小鼠动静脉瘘模型，我们 已经表明，先天免疫反应和获得性免疫反应都调节静脉 改建。我们提供了令人振奋的新数据，性激素在性别差异中起调节作用 静脉重塑。此外，我们还进一步发展了包括慢性肾脏的小鼠模型。 通过5/6肾切除的疾病(CKD)；CKD环境中的AVF显示静脉重构的改变 与对照组小鼠相比，这些动静脉曲张真实地概括了人动静脉曲张的成熟。我们假设，由于T 细胞介导静脉重构，调节获得性免疫会改变静脉重构，从而 改善动静脉瘘的通畅性，并最终提高人类患者的瘘管利用率。我们将使用我们的翻译 相关体内模型，一种将环孢素包裹在纳米粒中用于局部药物输送的创新工具， 创新的方法来分析AVF壁内的免疫细胞成分，以及先进的NEXT- 使用耶鲁大学提供的转录切分技术进行世代分析，以测试我们的创新 假设有以下具体目的： 目的I：确定男女获得性免疫的性别差异是否影响AVF 活体重塑。目的II：确定性激素是否在免疫反应中调节性别差异 在慢性肾脏病小鼠AVF重塑过程中。目的III：确定PD-L1的表达是否调节该效应 获得性免疫对慢性肾功能不全小鼠AVF重构的影响。 这次调查的成功结果将产生持久的影响，因为它将确定是否存在T 静脉重塑的细胞基础和获得性免疫的操纵是一种有价值的策略 临床翻译以提高动静脉动静脉瘘的通畅性。我们还将确定减少的AVF是否在 女性是由于在适应性免疫方面的性别差异。我们使用创新的战略和新颖的工具， 模型操纵适应性免疫以改变静脉重塑，从而改善动静脉瘘的通畅性。

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.