Abstract We0050: CCR4 Deficiency Decreases Arteriovenous Fistula Patency and Increases Venous Wall Thickness

Regulatory T cells (Treg) help regulate vascular biology and inflammation including in aneurysmal disease, atherosclerosis, and angiogenesis. While the roles of some immune cells such as the helper T cell, M1, and M2 macrophage have been shown to have an impact on arteriovenous (AV) fistula maturation and remodeling, the role of Tregs has not been as well studied during AV fistula maturation. C-C chemokine receptor type 4 (CCR4) is a chemokine receptor on Tregs responsive to CCL17 and CCL22 and is required for tissue recruitment and cellular interaction with dendritic cells. We hypothesized that inhibition of Treg function via inhibition of CCR4 leads to increased neointimal hyperplasia and thus impairs AV fistula maturation and remodeling. Aorto-caval fistulae were created in mice treated with the CCR4 inhibitor AF399/420/18 025 (n=13) or with DMSO as control (n=13) as well as in CCR4 -/- (n=8) and WT littermate controls (n=6). Aortic diameter, inferior vena cava (IVC) diameter, aortic peak velocity, and IVC peak velocity were measured at day 21 using duplex ultrasound. Venous wall thickness was measured using paraffin-embedded sections stained with Elastin van Gieson’s stain. There was reduced patency in the CCR4 inhibitor-treated mice while all 13 fistulae created in the control group remained patent (p=0.0792; day 42; Figure 1). Similarly, all 6 fistulae created in WT mice were patent by day 42 whereas 2 of 6 fistulae created in CCR4 -/- mice were not patent at day 21; the remaining 2 fistulae remained patent by day 42 (p=0.2024). There was no statistically significant difference among control mice and CCR4 inhibited or knockout mice in aortic diameter, IVC diameter, aortic peak velocity, and IVC peak velocity at day 21 (Figure 2). However, the relative thickness of the venous wall was increased in the fistulae of CCR4 inhibitor-treated mice compared to control (p=0.0015) and in CCR4 -/- compared to WT mice (p=0.0662; Figure 3). These results suggest that CCR4 deficiency results in decreased AV fistula patency and increased venous outflow wall thickness and imply that immunomodulation of Treg may be a novel approach to improve AVF patency.