Abstract
BackgroundCardiac allograft vasculopathy (AV) is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation. While there is consensus that AV is alloimmune mediated, and evidence that the most important alloimmune target is medial smooth muscle cells (SMC), the role of the innate immune response in the initiation of this disease is still being elucidated. As ischemia reperfusion (IR) injury plays a pivotal role in the initiation of AV, we hypothesize that IR enhances the early innate response to cardiac allografts.MethodsAortic transplants were performed between fully disparate mouse strains (C3H/HeJ and C57BL/6), in the presence of therapeutic levels of Cyclosporine A, as a model for cardiac AV. Neutrophils were depleted from some recipients using anti-PMN serum. Grafts were harvested at 1,2,3,5d and 1,2wk post-transplant. Ultrastructural integrity was examined by transmission electron microscopy. SMC and neutrophils were quantified from histological sections in a blinded manner.ResultsGrafts exposed to cold ischemia, but not transplanted, showed no medial SMC loss and normal ultrastructural integrity. In comparison, allografts harvested 1d post-transplant exhibited > 90% loss of SMC (p < 0.0001). SMC partially recovered by 5d but a second loss of SMC was observed at 1wk. SMC loss at 1d and 1wk post-transplant correlated with neutrophil influx. SMC loss was significantly reduced in neutrophil depleted recipients (p < 0.01).ConclusionsThese novel data show that there is extensive damage to medial SMC at 1d post-transplant. By depleting neutrophils from recipients it was demonstrated that a portion of the SMC loss was mediated by neutrophils. These results provide evidence that IR activation of early innate events contributes to the etiology of AV.
Highlights
Cardiac allograft vasculopathy (AV) is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation
Medial smooth muscle cells (SMC) are lost immediately post-transplantation To examine pathological events occurring immediately post-transplantation, aortic allografts were transplanted between fully disparate strain combinations (C3H to B6) with calcineurin inhibitor (CNI) immunosuppression
To examine the effect of cold ischemia on SMC we examined grafts after 20 min cold ischemia histologically and at the ultrastructural level using Transmission Electron Microscopy (TEM) (Fig 1c,d)
Summary
Cardiac allograft vasculopathy (AV) is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation. While there is consensus that AV is alloimmune mediated, and evidence that the most important alloimmune target is medial smooth muscle cells (SMC), the role of the innate immune response in the initiation of this disease is still being elucidated. As ischemia reperfusion (IR) injury plays a pivotal role in the initiation of AV, we hypothesize that IR enhances the early innate response to cardiac allografts. Significant improvements in early survival post-cardiac transplantation can be attributed to new developments in immunosuppressive therapies, rates of late rejection remain unchanged, yielding only 50% graft survival at 10 years post-transplant [2]. While few debate the critical role that T cells play in acute and chronic rejection of allografts, only recently have studies begun to acknowledge the extent to which the innate immune system regulates the potency and nature of allograft rejection [17,18]
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