Suppression of Murine Cardiac Allograft Arteriopathy by Long-Term Blockade of CD40-CD154 Interactions

Abstract

Background-The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure. Methods and Results-A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days Ϫ1, 1, and 3; long-term blockade consisted of MR1 given on days Ϫ1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43Ϯ7% and 50Ϯ12%, respectively (PϭNS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19Ϯ3% (PϽ0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control (PϽ0.05). Conclusions-These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.

C-Reactive Protein-Induced Expression of CD40–CD40L and the Effect of Lovastatin and Fenofibrate on It in Human Vascular Endothelial Cells

“…CD40-CD40L blockade has shown to prevent atherosclerotic plaque progression, to promote plaque stability and to prevent transplant associated vasculopathy, an accelerated form of atherosclerosis. 31,32) Our studies found that CRP, at concentration known to predict adverse cardiovascular events, caused a marked and dose-dependent increase in the cell-surface expression of CD40 and CD40L protein in HUVECs. Unstimulated HUVECs with CRP expressed lower level of CD40 and only a little CD40L, which was in accordance with previous report.…”

A20 Protects From CD40-CD40 Ligand-Mediated Endothelial Cell Activation and Apoptosis

“…By specifically interrupting this dyad, A20-based gene therapy in EC could, as demonstrated using anti-CD40L Ab therapy, significantly impact on the initiation and progression of atherosclerosis and TAV. 10,11,24 …”

“…9 In animal models, CD40L blockade has been shown to prevent atherosclerotic plaque progression, promote plaque stability, and prevent transplant associated vasculopathy (TAV), an accelerated form of atherosclerosis. 10,11 We have demonstrated that the cytoprotective gene A20, prevents EC activation in response to a number of stimuli (including proinflammatory cytokines and oxidative damage) by blocking NF-B activation and shown that it protects ECs from TNF/cycloheximide-induced apoptosis through inhibition of the caspase cascade. 12,13 In this study, we evaluate the effect of A20 on CD40/CD40L-mediated EC signaling and activation.…”

Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

“…Echocardiographic images were recorded in a digital format. Images were then analyzed off-line by a single observer blinded to the murine genotype (29).…”