RNase: A possible adjuvant in transplantation?

Objectives: Cell injury, particularly as consequence of ischemia/reperfusion or acute rejection after transplantation, leads to release of intracellular components like RNA. Extracellular RNA, causes edema as a result of increasing permeability of blood vessels, is described as a procoagulation factor by activation of the contact phase system leading to thrombus formation and vessel occlusion, and promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines, and thus, triggers immune response. In rodent models of stroke and thrombosis, treatment with counteracting RNase was shown with less edema and vessel occlusion. In search of additive drugs to protect grafts from dysfunction, we investigated if treatment with RNase in a rat model of heterotopic heart transplantation results in less edema and less coronary occlusion, and, therefore, in improved graft survival.

Methods: Brown Norway rat cardiac allografts were transplanted into the abdomen of Lewis rats. Microvascular technique for aorto-aortic and pulmonary artery to inferior vena cava anastomosis (Langendorff) was used. Recipients were intravenously treated directly before transplantation and every other day with RNase (50µg/kg) or vehicle (saline, n = 6/group). The primary end point of the study was the graft survival, which was determined by daily examination of the graft function by palpation and in case of inconclusiveness by echocardiography. A tolerance study was performed treating animals daily with RNase 50 µg/kg, with RNase 1000 µg/kg, or vehicle, respectively, for 28d (n = 3/group).

Results: Mean graft survival was 6.5 ± 0.55d in vehicle treated animals vs 10.2 ± 1.0d in RNase treated animals (p = 0.002). Directly after explantation donor grafts had a mean weight of 0.94 ± 0.03g. After been rejected donor graft weight increased to 2.06 ± 0.52g in vehicle treated recipients, in contrast to 1.28 ± 0.27g in RNase treated recipients (p = 0.017). The tolerance study showed neither macroscopic nor histological differences between treatment groups.

Conclusions: RNase significantly improved graft survival. Histological analyses in progress will help to clarify if RNase will keep the promise to reduce edema formation even in the field of transplantation, as suggested due to significant less graft weight in RNase treated recipients. On the basis of these sweeping results, however, we suppose that RNase could be a possible adjuvant in transplantation.