Abstract
BackgroundIschemia/reperfusion induced innate immune injury is inescapable in solid organ transplantation. Prolonged cold ischemia exacerbates the primary manifestation of late graft rejection, allograft vasculopathy (AV). The relationship between prolonged cold ischemia and late graft events is unclear and the subject of this study.MethodsAortic interposition transplants were performed between fully disparate mice treated with CyclosporineA. Allografts were exposed to 20 min or 60 min of cold ischemia and harvested between 1 d-6 wk. Lesion size, smooth muscle cells (SMC), neutrophils (N∅), and CD8+ T cells were quantified.ResultsEarly SMC loss was identical in both groups. When compared to 20 min cold ischemia, grafts exposed to 60 min exhibited greater early N∅ influx, greater SMC proliferation but fewer medial SMC at 1 wk and 2 wk. Subsequently, earlier and greater CD8+ T cell infiltration were seen in the 60 min group with larger lesions at every time point.ConclusionsThese data suggest that the larger neointimal lesions in grafts exposed to 60 min cold ischemia result from enhanced early innate immune events resulting in impaired SMC recovery and subsequent increased adaptive immune response.
Highlights
Despite the introduction of mechanical assist devices to stabilize cardiac function, cardiac transplantation remains the primary treatment for end stage heart failure
Prolonged cold ischemia leads to earlier lesion formation Earlier studies conducted in the absence of calcineurin inhibitor (CNI) immunosuppression provide evidence that prolonged CI exacerbates allograft vasculopathy (AV), resulting in larger neointimal lesions [18]
To confirm this in the presence of clinically relevant levels of CNI immunosuppression, we followed the progression of lesion formation in transplanted murine aortic allografts which had been exposed to either 20 or 60 min of CI and harvested1-6 wk post-transplant
Summary
Despite the introduction of mechanical assist devices to stabilize cardiac function, cardiac transplantation remains the primary treatment for end stage heart failure. The primary manifestation of late graft rejection in cardiac transplants is allograft vasculopathy (AV), observed predominantly in the large epicardial coronary vessels [2]. The etiology and pathology of AV are incompletely understood but it is characterized by vascular remodelling [2], including loss of medial smooth muscle cells (SMC) and the growth of a neointimal lesion. This lesion eventually narrows the vessel lumen and promotes thrombosis in the affected vessels. Prolonged cold ischemia exacerbates the primary manifestation of late graft rejection, allograft vasculopathy (AV). The relationship between prolonged cold ischemia and late graft events is unclear and the subject of this study
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