Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis

van Leuven, Sander I.; van Wijk, Diederik F.; Volger, Oscar L.; de Vries, Jean-Paul P.M.; van der Loos, Chris M.; de Kleijn, Dominique V.P.; Horrevoets, Anton J.G.; Tak, Paul P.; van der Wal, Allard C.; de Boer, Onno J.; Pasterkamp, Gerard; Hayden, Michael R.; Kastelein, John J.P.; Stroes, Erik S.

doi:10.1016/j.atherosclerosis.2010.01.043

« Previous Next »Atherosclerosis
Volume 211, Issue 1 , Pages 231-236, July 2010

Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis☆

Sander I. van Leuven
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- 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.
Diederik F. van Wijk
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Oscar L. Volger
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
Jean-Paul P.M. de Vries
- Department of Vascular Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands
Chris M. van der Loos
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Dominique V.P. de Kleijn
- Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands
Anton J.G. Horrevoets
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
Paul P. Tak
- Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Allard C. van der Wal
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Onno J. de Boer
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Gerard Pasterkamp
- Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands
Michael R. Hayden
- Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
John J.P. Kastelein
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Erik S. Stroes
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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.

Keywords: Inflammation, Atherosclerosis, Endarterectomy, Mycophenolate mofetil