高剂量和长时间的环孢素治疗可减轻啮齿动物心脏移植中移植冠状动脉疾病的严重程度。

Cyclosporine treatment of high dose and long duration reduces the severity of graft coronary artery disease in rodent cardiac allografts.

作者信息

Lijkwan Maarten A, Cooke David T, Martens Jasper M, Kown Murray H, Murata Seiichiro, Peterson Shannon H, Hoyt E Grant, Robbins Robert C

机构信息

Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.

出版信息

J Heart Lung Transplant. 2005 Apr;24(4):439-45. doi: 10.1016/j.healun.2004.01.020.

DOI:10.1016/j.healun.2004.01.020

PMID:15797746

Abstract

BACKGROUND

Graft coronary artery disease (GCAD) limits allograft survival after cardiac transplantation. The objective of this study was to correlate GCAD with the level of immunosuppression in an established allogeneic rodent cardiac chronic rejection model to better understand the mechanisms of GCAD in this system.

METHODS

Donor PVG hearts were transplanted into the abdomen of ACI rats. Six recipient groups received either 10, 7.5 or 5 mg/kg/day of oral cyclosporine (CsA), for 90 (10 mg/90 d, 7.5 mg/90 d, 5 mg/90 d) or 10 days (10 mg/10 d, 7.5 mg/10 d, 5 mg/10 d; n = 10 all groups), and grafts procured on Day 90. GCAD was assessed by histology for percent luminal narrowing (%LN), percent affected vessels (%AV) and intima/media ratio (I/M ratio). Sections were stained for ED1-positive macrophages and MHC Class II-positive cells.

RESULTS

The 10 mg/90 d treatment group showed significantly reduced GCAD compared with the 5mg/10d treatment group (%LN = 4.3 +/- 3.1% vs 39 +/- 11.9%, p < 0.05). The 7.5 mg/90 d group had a reduced %LN and I/M ratio compared with the 5 mg/10 d group (%LN = 8.0 +/- 3.5% vs 39 +/- 11.9%, p < 0.05; I/M ratio = 0.06 +/- 0.02 vs 0.41 +/- 0.14, p < 0.05). There was a trend toward reduction of GCAD with both increasing the dose of CsA as well as the duration of treatment. Continuous treatment with CsA reduced perivascular macrophage and MHC II cell infiltration. Macrophage infiltrates correlated strongly with GCAD (R(2) > 0.90, p < 0.01), and MHC II infiltrates showed a weak correlation, although not statistically significant (R(2) > 0.56, p = NS).

CONCLUSIONS

This study further defines the effect of cyclosporine on GCAD in this cardiac transplantation model. In this system, higher dose and longer duration of treatment with CsA markedly reduces macrophage and MHC II infiltration, correlating with diminished GCAD. However, increasing dose and duration of CsA did not completely eliminate the development of GCAD. Non-immunologic factors could contribute to this occurrence.

摘要

背景

移植冠状动脉疾病（GCAD）限制了心脏移植后的同种异体移植物存活。本研究的目的是在已建立的同种异体啮齿动物心脏慢性排斥模型中，将GCAD与免疫抑制水平相关联，以更好地理解该系统中GCAD的机制。

方法

将供体PVG心脏移植到ACI大鼠腹部。六个受体组分别接受10、7.5或5mg/kg/天的口服环孢素（CsA），持续90天（10mg/90天、7.5mg/90天、5mg/90天）或10天（10mg/10天、7.5mg/10天、5mg/10天；每组n = 10），并在第90天获取移植物。通过组织学评估GCAD，包括管腔狭窄百分比（%LN）、受累血管百分比（%AV）和内膜/中膜比值（I/M比值）。切片用ED1阳性巨噬细胞和MHC II类阳性细胞染色。

结果

与5mg/10天治疗组相比，10mg/90天治疗组的GCAD明显减轻（%LN = 4.3±3.1%对39±11.9%，p < 0.05）。与5mg/10天组相比，7.5mg/90天组的%LN和I/M比值降低（%LN = 8.0±3.5%对39±11.9%，p < 0.05；I/M比值 = 0.06±0.02对0.41±0.14，p < 0.05）。随着CsA剂量的增加以及治疗持续时间的延长，GCAD有减轻的趋势。CsA持续治疗可减少血管周围巨噬细胞和MHC II细胞浸润。巨噬细胞浸润与GCAD密切相关（R²> 0.90，p < 0.01），MHC II浸润显示出较弱的相关性，尽管无统计学意义（R²> 0.56，p = NS）。