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Background  Fractalkine receptor 1 (CX3CR1) mediates macrophage infiltration and accumulation, causing venous neointimal hyperplasia (VNH)/venous stenosis (VS) in arteriovenous fistula (AVF). The effect of blocking CX3CR1 using an anti–human variable VHH molecule (hCX3CR1 VHH, BI 655088) on VNH/VS was determined using a humanized mouse in which the human  CX3CR1  ( hCX3CR1 ) gene was knocked in (KI).    Methods  Whole-transcriptomic RNA sequencing with bioinformatics analysis was used on human stenotic AVF samples, C57BL/6J,  hCX3CR1  KI mice with AVF and CKD, and in  in vitro  experiments to identify the pathways involved in preventing VNH/VS formation after hCX3CR1 VHH administration.    Results  Accumulation of CX3CR1 and CD68 was significantly increased in stenotic human AVFs. In C57BL/6J mice with AVF, there was increased  Cx3cr1, Cx3cl1, Cd68 , and  Tnf-α  gene expression, and increased immunostaining of CX3CR1 and CD68. In hCX3CR1-KI mice treated with hCX3CR1 VHH molecule (KI-A), compared with vehicle controls (KI-V), there was increased lumen vessel area and patency, and decreased neointima in the AVF outflow veins. RNA-seq analysis identified TNF- α  and NF- κ B as potential targets of CX3CR1 inhibition. In KI-A–treated vessels compared with KI-V, there was decreased gene expression of  Tnf-  α ,  Mcp-1 , and  Il-1  β ; with reduction of  Cx3cl1 , NF- κ B, and  Cd68 ; decreased M1, Ly6C, smooth muscle cells, fibroblast-activated protein, fibronectin, and proliferation; and increased TUNEL and M2 staining. In cell culture, monocytes stimulated with PMA and treated with hCX3CR1 VHH had decreased  TNF-  α ,  CD68 , proliferation, and migration.    Conclusions  CX3CR1 blockade reduces VNH/VS formation by decreasing proinflammatory cues.

Anti Human CX3CR1 VHH Molecule Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mouse Model