Attenuation of transplant arteriosclerosis with clopidogrel is associated with a reduction of infiltrating dendritic cells and macrophages in murine aortic allografts.
Journal - Transplantation (United States )
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 (H2b) donor aortas were transplanted into CBA.J (H2k) 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.
|ISSN : ||1534-6080|
|Mesh Heading : ||Animals Antibodies, Monoclonal Antigens, CD Antigens, Differentiation Aorta, Abdominal Arteriosclerosis CD40 Ligand Cell Adhesion Molecules Chemotaxis Dendritic Cells Dose-Response Relationship, Drug Down-Regulation Histocompatibility Testing Intercellular Adhesion Molecule-1 Interleukin-6 Lectins, C-Type Macrophages Mice Mice, Inbred C57BL Mice, Inbred CBA P-Selectin Platelet Aggregation Inhibitors Platelet Glycoprotein GPIb-IX Complex Platelet Membrane Glycoproteins Platelet-Derived Growth Factor RNA, Messenger Receptors, Cell Surface Ticlopidine Transplantation, Homologous metabolism metabolism immunology pathology transplantation immunology pathology blood blood genetics immunology metabolism metabolism metabolism immunology blood immunology immunology metabolism metabolism metabolism pharmacology|
|Mesh Heading Relevant : ||drug effects prevention & control metabolism drug effects drug effects drug effects pharmacology analogs & derivatives|
Clopidogrel reduces the development of transplant arteriosclerosis.
Journal - The Journal of thoracic and cardiovascular surgery (United States )
BACKGROUND: Transplant arteriosclerosis, the hallmark feature of chronic rejection, is still the major limiting factor for the long-term success of heart transplantation. Platelets have been implicated to play a role in the pathogenesis of this disease. Therefore the aim of this study was to investigate whether platelet inhibition alone has a positive effect on the development of transplant arteriosclerosis. METHODS: Fully major histocompatibility complex-mismatched C57BL/6 (H2(b)) donor aortas were transplanted into CBA (H2(k)) recipients, and mice received different doses (1, 10, and 20 mg/kg) of clopidogrel or control saline as a daily intraperitoneal injection for 30 days. Blood was analyzed on days 2, 7, 14, and 30 by using a platelet aggregation test (adenosine diphosphate) for effectiveness of the treatment. Grafts were analyzed by means of histology and morphometry on day 30 after transplantation. RESULTS: When mice were treated daily with 1 mg/kg clopidogrel in the absence of any other immunosuppression, transplant arteriosclerosis was significantly reduced compared with that seen in saline-treated control animals (intimal proliferation of 66% +/- 9% [1 mg/kg clopidogrel] vs 77% +/- 5% [control], n = 7, P < or = .03). Daily application of 10 mg/kg and 20 mg/kg clopidogrel also significantly reduced the development of transplant arteriosclerosis compared with that seen in control animals (intimal proliferation of 61% +/- 11% [10 mg/kg clopidogrel] vs 54% +/- 10% [20 mg/kg clopidogrel] vs 77% +/- 5% [control], n = 8, P < or = .003). There was, however, no additional beneficial effect when compared with mice treated with 1 mg/kg clopidogrel (P = .06). Isografts did not show any signs of vascular lesions on day 30 after transplantation. CONCLUSION: These results demonstrate that monotherapy with clopidogrel can effectively reduce the formation of transplant arteriosclerosis in a murine aortic allograft model.
|ISSN : ||1097-685X|
|Mesh Heading : ||Animals Aorta Arteriosclerosis Disease Models, Animal Graft Rejection Mice Mice, Inbred C57BL Mice, Inbred CBA Platelet Aggregation Inhibitors Ticlopidine Transplantation, Homologous therapeutic use|
|Mesh Heading Relevant : ||transplantation prevention & control prevention & control therapeutic use analogs & derivatives|