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- Akyurek, M. L., et al.
(författare)
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Effects of angiopeptin on transplant arteriosclerosis in the rat
- 1995
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Ingår i: Transpl Int. ; 8:2, s. 103-10
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Tidskriftsartikel (refereegranskat)abstract
- The influence of the somatostatin analogue angiopeptin on transplant arteriosclerosis was investigated using two aortic transplantation rat models. One was characterized by ischemia/reperfusion-induced changes in syngeneic transplants while immunologically induced changes dominated in the other allogeneic model. Angiopeptin, 100 micrograms/kg per day, was administered continuously until the sacrifice of the rats after 8 weeks. No additional immunosuppression was used in either model. An image analysis system was used to quantify the intimal and medial thicknesses of the grafts. In the syngeneic grafts, the intimal thickness was less than 50% of that of control grafts (P < 0.05), but no difference was seen in the allogeneic model. The expression of selected cells, TGF-beta s, and PDGF and PDGF alpha-receptors was detected immunohistochemically and displayed a similar picture in control and angiopeptin-treated grafts in both models. We conclude that angiopeptin has no clear immunosuppressive properties but may counteract ischemia-induced transplant arteriosclerosis.
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- Waltenberger, J., et al.
(författare)
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Ischemia-induced transplant arteriosclerosis in the rat. Induction of peptide growth factor expression
- 1996
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Ingår i: Arterioscler Thromb Vasc Biol. ; 16:12, s. 1516-23
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Tidskriftsartikel (refereegranskat)abstract
- Peptide growth factors have been reported to contribute to the atherogenic process, and they are known to mediate signals for vascular remodeling. Using syngeneic and allogeneic rat aorta transplant models, we analyzed the impact of cold ischemia time up to 24 hours and reperfusion injury on development of transplant arteriosclerosis during the first 2 months after transplantation. The expression of the transforming growth factor-beta (TGF-beta) family as well as the platelet-derived growth factor (PDGF) and its receptors was studied by use of immunohistochemistry, followed by semiquantitative evaluation and multivariate analysis. In the syngeneically transplanted aortas, the expression of TGF-beta 1, PDGF, and the two PDGF receptors in the neointima increased significantly with the extent of cold ischemia time. Furthermore, there was a significant induction of the latent TGF-beta binding protein in the neointima as well as TGF-beta 2 in the media, both correlating with the observation time after transplantation. In the allogeneic grafts, all examined proteins were already induced strongly 2 weeks after transplantation, even at the shortest ischemic period studied (1 hour). However, no positive correlation between growth factor expression and cold ischemia or observation time could be found. Double immunohistochemistry revealed that macrophages express PDGF and its receptors as well as TGF-beta 1. Smooth muscle cells express both types of PDGF receptors, and a few T cells express TGF-beta 1 as well as PDGF receptors. In summary, TGF-beta and PDGF are induced by allogeneic as well as ischemic stimuli in transplanted aortas, suggesting a role in the pathogenesis of transplant arteriosclerosis and representing a potential target for therapeutic intervention.
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- Akyurek, L. M., et al.
(författare)
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Inhibition of transplant arteriosclerosis in rat aortic grafts by low molecular weight heparin derivatives
- 1995
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Ingår i: Transplantation. ; 59:11, s. 1517-24
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Tidskriftsartikel (refereegranskat)abstract
- The effects of low molecular weight heparin derivatives with a low anticoagulant activity on transplant arteriosclerosis (TA) in a rat aortic transplant model were investigated. TA was induced by ischemia in the syngeneic transplants and primarily by immunological mechanisms in the allogeneic transplants. Treatment with the heparin derivatives, OAM 71262 or LA-heparin, was administered in a dosage of 250 micrograms/kg/hr by mini-osmotic pumps during 8 weeks. No immunosuppressive regimen was given to the recipient rats in either model. All rats were killed 8 weeks after aortic grafting. The grafts were examined for intimal and medial changes using an image analysis system. Heparin derivatives had a beneficial effect on both the intimal thickening and the medial injury in the syngeneic transplants, but not in the allogeneic grafts. In the syngeneic LA-heparin treated grafts, the thickness of the intima was less than that in the syngeneic control grafts (P < 0.05). In the syngeneic transplants, a significant increase was observed in the media after treatment with OAM 71262 (P < 0.01) as well as those with LA-heparin (P < 0.001). In the syngeneic grafts treated with both heparin derivatives, a significant reduction in the antigen expression of alpha-actin-containing smooth muscle cells in the intima, transforming growth factor-beta 1 both in the media and adventitia, and platelet-derived growth factor-beta receptors in the adventitia was observed immunohistochemically. In summary, low molecular weight heparin derivatives with low anticoagulant activity partially inhibited ischemia-induced syngeneic TA, whereas no such effect could be demonstrated in nonimmunosuppressed recipients with allogeneic grafts.
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- Akyürek, L M, et al.
(författare)
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Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis.
- 1998
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Ingår i: The Journal of clinical investigation. - 0021-9738. ; 101:12, s. 2889-99
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Tidskriftsartikel (refereegranskat)abstract
- Based on successful induction of donor-specific unresponsiveness by alloantigenic stimulation in several animal models of acute rejection, we hypothesized that similar immune manipulations would also inhibit the evolution of chronic rejection and transplant vasculopathy. To induce immune tolerance, DA rats received a PVG heart allograft and were immunosuppressed with cyclosporine for 30 d. At day 100 the animals were challenged with a PVG aortic allograft after either 1 or 18 h of cold ischemia. 8 wk after the aortic transplantation, the grafts were investigated for morphological changes, infiltrating cells, apoptosis, and Fas-Fas ligand expression. Control allografts showed advanced transplant arteriosclerosis, whereas tolerance-induced aortic allografts displayed reduced neointimal formation, less medial atrophy, fewer apoptotic cells, and fewer Fas- and FasL-expressing cells. Prolonged ischemic storage time did not profoundly alter the morphological changes of the allografts. Fas expression was found in T cells, macrophages, vascular smooth muscle cells, and endothelial cells, whereas FasL was expressed mainly by T cells and macrophages. FasL mRNA expression was evident throughout the entire allograft wall. In conclusion, induction of allospecific tolerance can effectively prevent transplant arteriosclerosis. Cold ischemia damage does not abrogate the beneficial effect of tolerance, but creates a separate identity of mainly endothelial lesions. Furthermore, Fas-mediated apoptosis appears to be involved in the pathological lesions seen in chronic rejection.
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