Adaptive immunity regulates arteriovenous fistula remodeling

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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.