Attenuation of Transplant Arteriosclerosis With Clopidogrel Is Associated With a Reduction of Infiltrating Dendritic Cells and Macrophages in Murine Aortic Allografts

被引:42
作者
Abele, Silke [1 ]
Spriewald, Bernd M. [2 ]
Ramsperger-Gleixner, Martina [1 ]
Wollin, Martina [1 ]
Hiemann, Nicola E. [3 ]
Nieswandt, Bernhard [4 ]
Weyand, Michael [1 ]
Ensminger, Stephan M. [1 ]
机构
[1] Univ Erlangen Nurnberg, Dept Cardiac Surg, D-91054 Erlangen, Germany
[2] Univ Erlangen Nurnberg, Dept Med 5, D-91054 Erlangen, Germany
[3] Deutsch Herzzentrum Berlin, Dept Cardiothorac & Vasc Surg, Berlin, Germany
[4] Univ Wurzburg, DFG Res Ctr Expt Biomed, Rudolf Virchow Ctr, Wurzburg, Germany
关键词
Platelets; Transplant arteriosclerosis; Dendritic cells; Adhesion molecules; Clopidogrel; ADHESION MOLECULE-1; GROWTH-FACTOR; P-SELECTIN; HEART-TRANSPLANTATION; PLATELET ACTIVATION; ENDOTHELIAL-CELLS; CHRONIC REJECTION; TISSUE-INJURY; IN-VIVO; IDENTIFICATION;
D O I
10.1097/TP.0b013e3181938913
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Monotherapy with clopidogrel reduced the formation of transplant arteriosclerosis in a murine aortic allograft model. However, the underlying immunologic mechanisms are still unknown. Methods. Fully major histocompatibility complex-mismatched C57BL/6 (H2(b)) donor aortas were transplanted into CBA.J (H2(k)) recipients and mice received different doses (1, 10, and 20 mg/kg) of clopidogrel, an antagonist of the P2Y12 ADP receptor on platelets, or control saline for 30 days. Blood was analyzed for changes in adhesion molecule and sCD40L concentrations by ELISA. Grafts were analyzed by histology, morphometry, and immunofluorescence on day 30 after transplantation. Intragraft cytokine mRNA production was analyzed by reverse-transcriptase polymerase chain reaction on day 14 after transplantation. Results. Treatment with clopidogrel resulted in significantly decreased blood concentrations of sCD40L and P-selectin after transplantation. Cellular analysis of the aortic transplant revealed fewer numbers of infiltrating dendritic cells (CD205(+)) and macrophages (F4/80(+)) after application of clopidogrel, whereas T-cells within the graft were unaltered. In addition cellular P-/E-selectin, ICAM-1, and platelet-derived-growth-factor (PDGF)-beta surface expression were significantly reduced as compared with untreated controls. Intragraft mRNA expression confirmed these results and showed significant lower production of P-/E-selectin, ICAM-1, and PDGF-beta after treatment with clopidogrel. Antiglycoprotein-Ib and antiglycoprotein VI had no beneficial effect on the development of transplant arteriosclerosis. Conclusion. This report shows that application of clopidogrel after transplantation results in a reduction in adhesion molecule expression within the blood and transplant tissue and is associated with reduced transendothelial migration of dendritic cells and macrophages within the vascular wall.
引用
收藏
页码:207 / 216
页数:10
相关论文
共 39 条
[1]   Clopidogrel reduces the development of transplant arteriosclerosis [J].
Abele, S ;
Weyand, M ;
Wollin, M ;
Hiemann, NE ;
Harig, F ;
Fischlein, T ;
Ensminger, SM .
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 2006, 131 (05) :1161-1166
[2]   Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions [J].
Bobryshev, YV ;
Lord, RSA .
CARDIOVASCULAR RESEARCH, 1998, 37 (03) :799-810
[3]   Mouse model of transplant arteriosclerosis - Role of intercellular adhesion molecule-1 [J].
Dietrich, H ;
Hu, YH ;
Zou, YP ;
Dirnhofer, S ;
Kleindienst, R ;
Wick, G ;
Xu, QB .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (02) :343-352
[4]   Kinetics of transplant arteriosclerosis in MHC-class I mismatched and fully allogeneic mouse aortic allografts [J].
Ensminger, SM ;
Spriewald, BM ;
Witzke, O ;
Morrison, K ;
Pajaro, OE ;
Morris, PJ ;
Rose, ML ;
Wood, KJ .
TRANSPLANTATION, 2002, 73 (07) :1068-1074
[5]   CD8+ T cells contribute to the development of transplant arteriosclerosis despite CD154 blockade [J].
Ensminger, SM ;
Witzke, O ;
Spriewald, BM ;
Morrison, K ;
Morris, PJ ;
Rose, ML ;
Wood, KJ .
TRANSPLANTATION, 2000, 69 (12) :2609-2612
[6]  
Fateh-Moghadam S, 2000, CIRCULATION, V102, P890
[7]   Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium [J].
Gawaz, M .
CARDIOVASCULAR RESEARCH, 2004, 61 (03) :498-511
[8]   A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) [J].
Gent, M ;
Beaumont, D ;
Blanchard, J ;
Bousser, MG ;
Coffman, J ;
Easton, JD ;
Hampton, JR ;
Harker, LA ;
Janzon, L ;
Kusmierek, JJE ;
Panak, E ;
Roberts, RS ;
Shannon, JS ;
Sicurella, J ;
Tognoni, G ;
Topol, EJ ;
Verstraete, M ;
Warlow, C .
LANCET, 1996, 348 (9038) :1329-1339
[9]   Close relationship between the platelet activation marker CD62 and the granular release of platelet-derived growth factor [J].
Graff, J ;
Klinkhardt, L ;
Schini-Kerth, VB ;
Harder, S ;
Franz, N ;
Bassus, S ;
Kirchmaier, CM .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 300 (03) :952-957
[10]   The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40 [J].
Henn, V ;
Steinbach, S ;
Büchner, K ;
Presek, P ;
Kroczek, RA .
BLOOD, 2001, 98 (04) :1047-1054