Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis☆
Received 13 August 2009; received in revised form 3 December 2009; accepted 29 January 2010. published online 04 March 2010.
Abstract
Atherosclerosis as well as the subsequent progression towards cardiovascular events are considered to, at least partially, be a consequence of chronic inflammatory activity. Therefore, we decided to evaluate the impact of short-term immunosuppressive treatment on plaque characteristics in patients with symptomatic carotid artery stenosis.
Twenty-one patients were randomized to receive either 1000mg. Mycophenolate mofetil (MMF) BD or placebo for at least 2 weeks prior to undergoing carotid endarterectomy (CEA). The serial sections of the CEA specimens were immunostained for activated T-cells (CD3+CD69+), regulatory T-cells (CD3+FOXP3+) and macrophages (CD68). In addition, gene expression profiling was performed by Illumina gene-array.
Immunostaining revealed a reduction of activated T-cells in nine MMF-treated patients compared to 11 placebo-treated control patients (19.7% vs. 28.1%; p<0.05) as well as an increase of regulatory T-cells (3.8% vs. 1.8%; p=0.05). Microarray analyses confirmed beneficial changes to plaque phenotype, showing reduced expression of pro-inflammatory genes. Significantly reduced expression of metalloproteinases and osteopontin was observed in three out of nine MMF-treated patients compared to nil out of 11 in the placebo group.
In the present study we show that immunosuppressive treatment for two-and-a-half weeks prior to CEA elicits changes in the plaque phenotype of symptomatic patients. These changes include reduced inflammatory cell presence with a concomitant decrease in pro-inflammatory gene expression.
aDepartment of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
bDepartment of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
cDepartment of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
dDepartment of Vascular Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands
eDepartment of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
fDepartment of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands
gCentre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
Corresponding author at: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 020 5662377; fax: +31 020 5669343.