Lemström K, Koskinen P, Krogerus L, Daemen M, Bruggeman C, Häyry P
Transplantation Laboratory, University of Helsinki, Finland.
Circulation. 1995 Nov 1;92(9):2594-604. doi: 10.1161/01.cir.92.9.2594.
Cardiac allograft arteriosclerosis is the primary cause of late death in heart transplant recipients. Clinical studies have suggested that humoral and cellular immune response, hyperlipidemia, and cytomegalovirus (CMV) infection may amplify the disease. In this study, the role of CMV infection in the development of rat cardiac allograft arteriosclerosis is investigated.
Heterotopic rat cardiac allografts were performed from the DA to the WF rat strains. To prevent rejection, the recipients received triple-drug (cyclosporine A 20 mg.kg-1.d-1, azathioprine 2 mg.kg-1.d-1, and methylprednisolone 0.5 mg.kg-1.d-1) immunosuppression postoperatively. Recipient rats were infected intraperitoneally (n = 21) with 10(5) plaque-forming units of rat CMV (RCMV) 1 day after transplantation or were left uninfected and used as controls (n = 18). The grafts were removed 7 and 14 days and 1 and 3 months after transplantation. In 42% (9 of 21) of cardiac allografts in RCMV-infected rats, an intramural, mononuclear cell inflammation of small intramyocardial arterioles was observed compared with none in uninfected rats (P = .005). Acute RCMV infection was associated with an early perivascular inflammatory cell response of helper T (W3/25), cytotoxic T (OX8), and NK (3.2.3) cells, macrophages (OX42), and major histocompatibility complex class II expression around small intramyocardial arterioles and capillaries. No upregulation of interleukin-2 receptor expression was seen. In arteries and small intramyocardial arterioles, RCMV infection was associated with a significant endothelial cell proliferation and a clear increase in intimal thickening. Significant endothelial cell proliferation was also observed in the capillaries after RCMV infection. Immunohistochemistry revealed specific focal RCMV early and late antigen expression in epicardial and interstitial ED1-immunoreactive mononuclear cell infiltrates and around small arterioles of RCMV-infected cardiac allografts. Occasionally, media cells of stenosed small intramyocardial arterioles also showed strong focal RCMV antigen expression. In addition, infectious RCMV could be recovered by plaque assay in cardiac allografts expressing RCMV antigens.
These results demonstrate a productive RCMV infection in cardiac allograft structures and suggest that RCMV infection accelerates cardiac allograft arteriosclerosis, particularly in small intramyocardial arterioles mediated by inflammatory responses in the vascular wall and perivascular space.
心脏移植后同种异体移植血管硬化是心脏移植受者晚期死亡的主要原因。临床研究表明，体液和细胞免疫反应、高脂血症以及巨细胞病毒（CMV）感染可能会加剧这种疾病。在本研究中，探讨了CMV感染在大鼠心脏同种异体移植血管硬化发展中的作用。
将DA大鼠的心脏异位移植到WF大鼠体内。为防止排斥反应，受体大鼠术后接受三联药物（环孢素A 20 mg·kg-1·d-1、硫唑嘌呤2 mg·kg-1·d-1和甲泼尼龙0.5 mg·kg-1·d-1）免疫抑制。移植后1天，受体大鼠腹腔内注射10(5)个大鼠CMV（RCMV）空斑形成单位（n = 21），或不进行感染作为对照（n = 18）。在移植后7天、14天、1个月和3个月取出移植物。在感染RCMV的大鼠中，42%（21只中的9只）的心脏同种异体移植中观察到心肌内小动脉壁内单核细胞炎症，而未感染大鼠中未观察到（P = .005）。急性RCMV感染与心肌内小动脉和毛细血管周围辅助性T细胞（W3/25）、细胞毒性T细胞（OX8）、自然杀伤细胞（3.2.3）、巨噬细胞（OX42）的早期血管周围炎症细胞反应以及主要组织相容性复合体II类表达有关。未观察到白细胞介素-2受体表达上调。在动脉和心肌内小动脉中，RCMV感染与显著的内皮细胞增殖和内膜增厚明显增加有关。RCMV感染后，毛细血管中也观察到显著的内皮细胞增殖。免疫组织化学显示，在RCMV感染的心脏同种异体移植的心外膜和间质ED1免疫反应性单核细胞浸润以及小动脉周围有特异性局灶性RCMV早期和晚期抗原表达。偶尔，狭窄的心肌内小动脉的中膜细胞也显示出强烈的局灶性RCMV抗原表达。此外，在表达RCMV抗原的心脏同种异体移植中，通过空斑试验可回收感染性RCMV。
这些结果表明RCMV在心脏同种异体移植结构中发生了有效感染，并提示RCMV感染加速了心脏同种异体移植血管硬化，特别是在由血管壁和血管周围间隙的炎症反应介导的心肌内小动脉中。
