Elucidation of accelerated atherosclerosis in cardiac transplantation

心脏移植患者动脉粥样硬化加速是影响移植物存活的主要限制因素，并将严重导致供体短缺。免疫机制被认为在这一机制中起重要作用。动脉粥样硬化的易感性不同的近亲饲养的小鼠品系喂动脉粥样硬化的饮食。SJL/J小鼠具有动脉粥样硬化抗性，B10S小鼠具有动脉粥样硬化易感性。这种差异归因于未识别的Ath 7等位基因，与血清高密度脂蛋白（HDL）水平无关，表明Ath 7可能位于血细胞中。为了研究骨髓来源细胞在动脉粥样硬化发展中的作用，我们制备了辐照骨髓嵌合体，其中用SJL/J或B10S骨髓细胞和同源载子E-/-骨髓细胞重建受辐照的小鼠载子E-/-骨髓细胞。将载脂蛋白E-/- BM细胞移植建立混合嵌合，使免疫耐受细胞具有稳定的耐受性。在这两种嵌合体中，观察到主动脉粥样硬化病变明显减少，这可能是由于来自SJL/J或B10S的BM来源细胞对脂蛋白清除的增加。然而，由于载脂蛋白E-/-受体给予抗动脉粥样硬化的SJL/J骨髓细胞的血清非高密度脂蛋白水平高于给予易感的B10S骨髓细胞的血清非高密度脂蛋白水平，因此认为SJL/J骨髓细胞的脂质吸收效率较低。这些结果表明，BM来源的细胞脂质摄取效率是SJL/J株动脉硬化病变的关键决定因素。本研究结果将显著有助于制定新的策略，以减少心脏移植患者观察到的加速动脉粥样硬化，并有助于显着改善供体短缺的情况。

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.