Elucidation of accelerated atherosclerosis in cardiac transplantation

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Accelerated atherosclerosis observed in cardiac transplantation patients is a major limiting factor for graft survival, and will seriously contribute to the shortage of donors. Immune mechanism is considered to be strongly involved in this mechanism. Atherosclerosis susceptibility differs among inbred mouse strains fed an atherogenic diet. SJL/J mice are atherosclerosis resistant and B10S mice are atherosclerosis susceptible. This difference is attributed to unidentified Ath 7 allele independent of serum high-density lipoprotein (HDL) levels, suggesting that Ath 7 might be located in blood cells. To examine the roles of bone marrow (BM) derived cells in the development of atherosclerosis, we prepared irradiation BM chimeras where irradiated recipients, apo E-/- mice, were reconstituted with SJL/J or B10S BM cells plus syngeneic apo E-/- BM cells. The apo E-/- BM cells were transplanted to establish mixed chimerism, which resulted in stable tolerance in the immunocompetent cells. In both chimeras marked reductions of aortic atherosclerotic lesions were observed, which might be attributed to the increase in lipoprotein clearance by BM derived cells from SJL/J or B10S. However, since serum non-HDL levels was higher in apo E-/- recipients given atherosclerotsis resistant SJL/J BM cells than those given susceptible B10S BM cells, BM derived cells of SJL/J were considered to take lipids less efficiently. These results suggest that efficiency of lipid uptake by BM derived cells is a key determinant of athrosclerosis lesion in SJL/J strain. The results obtained in this study will significantly contribute to the development of new strategies to reduce the accelerated atherosclerosis observed in cardiac transplantation patients, and help to markedly improve the situation of donor shortage.