Co-stimulatory treatment enhances the protective role of CD8 and CD4 t cells in murine vein grafts

Background and Aims : Background Vein grafts are frequently used to bypass coronary artery occlusions. Unfortunately, vein graft disease (VGD) causes impaired patency that rapidly declines due to extensive intimal hyperplasia (IH). T-cells demonstrate both pro-and anti-atherogenic effects. Therefore, we investigated T-cell involvement in a mouse-model for VGD using pharmacological targeting of the co-stimulatory factor CD137.Methods: Methods Hypercholesterolemic male ApoE3*Leiden mice underwent vein graft surgery and were treated once with agonistic CD137-antibodies (200ug;S.C.) (n=9/group) or treated twice a week with antagonistic CD137L (200ug;S.C.) (n=9/group). Flow cytometry was performed on blood and non-invasive ultrasound was performed weekly until sacrifice (t28). Vein grafts were processed for morphometric and histological analysis or processed for flow cytometry.Results: Results Flow cytometry showed increased CD43 glycosylation on both CD4 (5.2-fold, p:0.005) and CD8 (3.5-fold, p:0.01) T-cells systemically after CD137 treatment. Ultrasound analysis showed a 1.7-fold increase (p:0.006) in lumen area after CD137 treatment at t21 and increased by 2.0-fold (p:0.004) at t28. Notably, CD137L treated vein grafts showed a decrease in lumen area, both confirmed histologically. Moreover, agonistic CD137 treatment increased smooth muscle cell accumulation by 18% at t28. Although no differences were observed in the macrophage lesion area after agonistic CD137 treatment. T-cells in the vein grafts from CD137 treated mice showed an increase in IFN-y+ cells, indicating an increase in Th1 and Tc1 cells.Conclusions: Conclusions Activation of T cells via CD137 enhanced T-cell activation, local IFN-y upregulation and an increased vein graft lumen. Activation of T-cells via CD137 is an attractive target to treat VGD. Background and Aims : Background Vein grafts are frequently used to bypass coronary artery occlusions. Unfortunately, vein graft disease (VGD) causes impaired patency that rapidly declines due to extensive intimal hyperplasia (IH). T-cells demonstrate both pro-and anti-atherogenic effects. Therefore, we investigated T-cell involvement in a mouse-model for VGD using pharmacological targeting of the co-stimulatory factor CD137. Methods: Methods Hypercholesterolemic male ApoE3*Leiden mice underwent vein graft surgery and were treated once with agonistic CD137-antibodies (200ug;S.C.) (n=9/group) or treated twice a week with antagonistic CD137L (200ug;S.C.) (n=9/group). Flow cytometry was performed on blood and non-invasive ultrasound was performed weekly until sacrifice (t28). Vein grafts were processed for morphometric and histological analysis or processed for flow cytometry. Results: Results Flow cytometry showed increased CD43 glycosylation on both CD4 (5.2-fold, p:0.005) and CD8 (3.5-fold, p:0.01) T-cells systemically after CD137 treatment. Ultrasound analysis showed a 1.7-fold increase (p:0.006) in lumen area after CD137 treatment at t21 and increased by 2.0-fold (p:0.004) at t28. Notably, CD137L treated vein grafts showed a decrease in lumen area, both confirmed histologically. Moreover, agonistic CD137 treatment increased smooth muscle cell accumulation by 18% at t28. Although no differences were observed in the macrophage lesion area after agonistic CD137 treatment. T-cells in the vein grafts from CD137 treated mice showed an increase in IFN-y+ cells, indicating an increase in Th1 and Tc1 cells. Conclusions: Conclusions Activation of T cells via CD137 enhanced T-cell activation, local IFN-y upregulation and an increased vein graft lumen. Activation of T-cells via CD137 is an attractive target to treat VGD.