| Tissue Engineered Vascular Grafts (TEVGs) hold great promise in advancing the field of pediatric cardiac surgery and other applications in which a vascular conduit is required. The first human clinical trial of these grafts indicated that stenosis was the primary mode of graft failure. Here, we investigate the role of the immune response in stenosis through a CB17 murine inferior vena cava interposition model. We demonstrate that this mouse model undergoes a dramatic stenotic response, and that this is nearly completely abolished in a SCID/bg immunodeficient variant (average luminal diameter (LD) WT: 0.071+/-0.035mm, SCID/bg: 0.804+/-0.039mm; P<0.001). SCID-only mice, which lack T- cells and B-cells, undergo stenosis with luminal diameters approaching those of wild type mice. The bg mutation is characterized by defects in natural killer (NK) cell and platelet dysfunction, and treatment of wild-type mice with either antiplatelet therapy (aspirin/clopidogrel) or an anti- natural killer cell antibody (NK 1.1) results in patency that is half of that achieved in the SCID/bg mouse (WT: 0.071+/- 0.035mm, SCID/bg: 0.804+/-0.039mm, SCID: 0.137+/-0.032mm, Asp/Pla: 0.452+/- 0.130mm, NKab: 0.356+/-0.151mm; P<0.001). We additionally show that SCID/bg mice show a blunted immune response to scaffold implantation, wheras wild-type mice show a dramatic initial burst of activity as demonstrated by macrophage number, mRNA, and cytokine levels. Implicating the initial innate immune response to the scaffold as a critical contributing factor in graft stenosis may provide a strategy for prognosis and therapy of future TEVGs. |
