Abstract
Allograft vasculopathy (AV) remains a major obstacle to long-term allograft survival. While the mouse aortic transplantation model has been proven as a useful tool for study of the pathogenesis of AV, simultaneous transplantation of the aorta alongside the transplantation of another organ may reveal more clinically relevant mechanisms that contribute to the pathogenesis of chronic allograft rejection. Therefore, we developed a combined abdominal heart and aorta transplantation model in mice which benefits from reducing animal and drug utilization, while providing an improved model to study the progressive nature of AV. The middle of the infrarenal aorta of the recipient mouse was ligatured between the renal artery and its bifurcation. Proximal and distal aortotomies were performed at this site above and below the ligature, respectively, for the subsequent anastomoses of the donor aorta and heart grafts to the recipient infrarenal aorta in an end-to-side fashion. The distal anastomotic site of the recipient infrarenal aorta was connected with the outlet of the donor aorta. Uniquely, the proximal anastomotic site on the recipient infrarenal aorta was shared to connect with both the inlet of the donor aorta and the inflow tract to the donor heart. The outflow tract from the donor heart was connected to the recipient inferior vena cava (IVC). The median times for harvesting the heart graft, aorta graft, recipient preparation and anastomosis were 11.5, 8.0, 9.0 and 40.5 min, respectively, resulting in a total median ischemic time of 70 min. The surgery survival rate was more than 96% (29/30). Both the syngeneic C57Bl/6 aorta and heart grafts survived more than 90 days in 29 C57Bl/6 recipients. Further, Balb/c to C57Bl/6 allografts treated with anti-CD40L and CTLA4.Ig survived more than 90 days with a 100% (3/3) survival rate. (3/3). This model is presented as a new tool for researchers to investigate transplant immunology and assess immunosuppressive strategies. It is possible to share a common anastomotic stoma on the recipient abdominal aorta to reconstruct both the aorta graft entrance and heart graft inflow tract. This allows for the study of allogeneic effects on both the aorta and heart from the same animal in a single survival surgery.
Highlights
Solid organ transplantation is one of the only viable interventions for patients with end-stage organ failure
Balb/c to C57Bl/6 allografts treated with anti-CD40L and CTLA4.Ig survived more than 90 days with a 100% (3/3) survival rate. (3/3)
Beyond acute rejection, which is most prevalent in the first year post-transplantation and can be actively managed with adjustments in immunosuppressive regimen or induction therapy [1, 2], the long term survival of transplanted hearts is impeded by graft failure, malignancy, cardiac allograft vasculopathy (CAV) and renal failure [1, 2]
Summary
Solid organ transplantation is one of the only viable interventions for patients with end-stage organ failure. Chronic allograft rejection remains one of the leading causes of graft failure one year post-transplantation [1, 2]. Chronic allograft injury leading to graft failure and CAV remains a major obstacle to the long-term allograft survival [1, 2, 4]. CAV is initiated by a combination of ischemia/reperfusion injury and alloimmune injury which results in endothelial dysfunction [5, 6] This leads to a progressive fibroproliferative disease with intimal smooth muscle cell proliferation leading to progressive vessel occlusion, thrombotic events and eventual graft failure [5, 6]. We developed a combined abdominal heart and aorta transplantation model in mice which benefits from reducing animal and drug utilization, while providing an improved model to study the progressive nature of AV
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