Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats

BACKGROUND: Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at five years post-transplantation. To date there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of thalidomide on the development of CAV.

METHODS: The effect of thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n=6/group). Animals were left untreated or received thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements.

RESULTS: Animals that received thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after thalidomide treatment revealed down-regulation of matrix metalloproteinase 8 (MMP-8) and monocyte chemotactic protein 1 (MCP-1), cytokines involved in tissue remodeling and inflammation, respectively. Importantly, no negative side effects of thalidomide were observed.

CONCLUSIONS: Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection.