Programmed death-1 mediates venous neointimal hyperplasia in humans and rats

Abstract

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.