Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model.
Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model.
复制标题
雷帕霉素在新型心脏同种异体移植模型中逆转慢性移植血管疾病。
DOI：
10.1161/01.cir.100.1.67
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发表时间：
1999
期刊：
影响因子：
37.8
通讯作者：
R. Robbins
中科院分区：
文献类型：
--
作者：
R. Poston;M. Billingham;E. Hoyt;J. Pollard;R. Shorthouse;R. Morris;R. Robbins
背景
心脏移植物中的慢性移植物血管病(CGVD)被定义为一种对常规免疫抑制无反应的缓慢发展的血管病变。我们比较了4种CGVD的啮齿动物模型，以评估CGVD在心脏移植中的重复性。用雷帕霉素(RapA)和环孢素A(CsA)治疗CGVD。
方法和结果
采集心脏并将其异位植入同种异体受体。接受CsA治疗的ACI患者PVG移植的CGVD评分在第90天(n=16)显著高于其他模型(使用免疫抑制)：(1)Lewis至F344受体(CSA)，(2)Brown挪威至Lewis(FK506)，(3)DA至Wistar-Firth(甲基强的松龙，硫唑嘌呤，CSA)。虽然延迟(第60天到90天)CsA治疗没有效果(n=6)，但延迟的Rapa(3 mg.Kg-1。D-1 ip)可逆转PVG移植物CGVD(第90天为0.22+/-0.19，n=6)。第90天，ACI同种异体移植未发现CGVD(n=6)。PVG移植物的免疫组织化学显示血管周围由CD4(+)T细胞和数量有限的巨噬细胞组成的浸润物持续到第90天。流式细胞术显示，在第90天，抗供体抗体水平升高，这一水平被RAPA显著抑制。
结论
PVG移植物的CGVD显著增加，没有持续的心肌排斥反应的证据。这种CGVD似乎是由细胞和体液机制介导的，考虑到CD4(+)血管周围的浸润物和增加的抗供体抗体水平。RAPA在心肌细胞浸润量较少的时期的抗CGVD作用支持一种新的作用机制，如平滑肌或B细胞抑制。
BACKGROUND
Chronic graft vascular disease (CGVD) in cardiac allografts has been defined as a slowly evolving vasculopathy unresponsive to conventional immunosuppression. We compared 4 rodent models of CGVD to evaluate the reproducibility of CGVD in heart allografts. Rapamycin (Rapa) and cyclosporine (CSA) were then used to treat CGVD.
METHODS AND RESULTS
Hearts were harvested and placed heterotopically into allogenic recipients. CGVD scores of PVG allografts from ACI recipients treated with CSA on days 1 through 10 were significantly elevated on day 90 (n=16) compared with other models (immunosuppression used): (1) Lewis to F344 recipients (CSA), (2) Brown Norway to Lewis (FK506), and (3) DA to Wistar-Firth (methylprednisolone, azathioprine, CSA). Although delayed (day 60 to 90) CSA treatment had no effect (n=6), delayed Rapa (3 mg. kg-1. d-1 IP) reversed CGVD in PVG grafts (0.22+/-0.19 on day 90, n=6). ACI isografts showed no evidence of CGVD (n=6) at day 90. Immunohistochemistry of PVG grafts revealed perivascular infiltrates consisting of CD4(+) T cells and limited numbers of macrophages persisting up to day 90. Flow cytometry demonstrated increased levels of anti-donor antibody at day 90, which was significantly inhibited by Rapa treatment.
CONCLUSIONS
PVG grafts developed a significant increase in CGVD without evidence of ongoing myocardial rejection. This CGVD appeared to be mediated by both cellular and humoral mechanisms, given CD4(+) perivascular infiltrates and increased levels of anti-donor antibody. The anti-CGVD effectiveness of Rapa during a period in which there was little myocardial cellular infiltrate supports a novel mechanism of effect such as smooth muscle or B-cell inhibition.
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