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  • Title: Cyclosporine treatment of high dose and long duration reduces the severity of graft coronary artery disease in rodent cardiac allografts.
    Author: Lijkwan MA, Cooke DT, Martens JM, Kown MH, Murata S, Peterson SH, Hoyt EG, Robbins RC.
    Journal: J Heart Lung Transplant; 2005 Apr; 24(4):439-45. PubMed ID: 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.
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