Additive and synergistic effects of a low-molecular-weight, heparin-like molecule and low doses of cyclosporin in preventing arterial graft rejection in rats.

Abstract

Arteriosclerotic intimal proliferation is one of the main long-term complications of organ transplantation. Low-molecular-weight, heparin-like molecules prevent myointimal proliferation in arterial wall injury and limit rejection in skin allografts. Cyclosporin limits rejection but has no major effect on intimal proliferation. Therefore, an experimental protocol was designed to test whether heparin-like molecules interacted with low doses of cyclosporin to prevent arterial wall immune system injury and response in a model of arterial graft rejection in normotensive and hypertensive rats. Aortic allografts were performed in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) normotensive control rats. Four groups of 10 allografted (SHR and WKY) rats were used: one group was treated with placebo, one with low doses of cyclosporin (2 nig/kg body wt per day), one with low-molecular-weight, heparin-like molecule (1 nig/kg body wt per hour), and one with low doses of cyclosporin plus low-molecular-weight, heparin-like molecule. Ten SHRs and 10 WKYs were isografted and served as the control groups. All rats were killed 8 weeks after aortic grafting. Structural parameters of the grafted segment were measured by morphometric analysis on formalin-fixed sections with specific stains. The classical signs of immune system injury and response were present in the untreated allografts in SHRs and WKYs: inflammatory infiltration of the adventitia, medial injury, and intimal proliferative response. Low doses of cyclosporin had a significant beneficial effect on immune medial injury by increasing medial thickness and the number of remaining smooth muscle cells and decreasing the extracellular matrix injury. Cyclosporin had no protective effect on intimal proliferation. Low-molecularweight, heparin-like molecules had a beneficial effect on both the medial injury and the intimal proliferative response that was independent of blood pressure. Heparin-like molecules increased medial thickness and partially prevented smooth muscle cell loss and extracellular matrix attack. They also significantly decreased the intimal thickness by acting more on the collagen content than on the smooth muscle cell density. Low doses of cyclosporin plus heparin-like molecules had a marked effect in preventing the arterial wall injury and response. This combination resulted in a normal medial appearance, increased medial thickness and smooth muscle cell number, and no intimal proliferation or adventitial inflammation. Thus, heparin-like molecules appear to act in concert with low doses of cyclosporin in preventing rejection-induced arterial wall remodeling in an experimental model of aortic allograft in rats, and their effects are independent of blood pressure. (Arteriosclerosis and Thrombosis 1993;13:112-119)

Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

“…Here, we show that the preventive and curative effects of CsA on AAAs are paralleled with aortic wall VSMC accumulation. Those results are compatible with the fact that one hallmark of CsA-induced vasculopathy in organ transplantation is the inappropriate accumulation of VSMCs [29]. Most importantly, in our study, the blocking antibody strategy credit the notion that CsA-induced TGF-beta1 preserves and restores VSMC content in AAAs, while controlling inflammation and proteolysis.…”

Cyclosporin suppresses transplant arteriosclerosis in the aorta-allografted, cholesterol-clamped rabbit. Suppression preceded by decrease in arterial lipoprotein permeability.

“…Using aorta-allografted rats, Mennander et al 18 found a transient worsening of transplant arteriosclerosis by cyclosporin treatment; others found no effect 1719 or an inhibiting effect 20 that disappeared after discontinuation of the treatment. One explanation for this discrepancy could be that studies with either a worsening effect or no effect used the lowest doses of cyclosporin (2 mg/kg SC, 17 5 mg/kg PO, 18 or 5 mg/kg SC, 19 ), whereas the one study with a reducing effect used a higher dose of cyclosporin (10 mg/kg SC 20 ). The latter dose is similar to the 8 to 10 mg/kg IM used in the present study.…”

Pathogenesis and Treatment Perspectives of Chronic Graft Rejection (CVR)

“…However, a protection of the vascular endothelium by heparin and heparin derivatives seems to be present. The effect upon transplant intimal hyperplasia has been demonstrated experimentally with low molecular weight heparin in combination with cyclosporine (Plissonnier et al 1992) and according to our own experience there are heparin derivatives without anticoagulant effects, which efficiently protect aorta grafts against development of intimal hyperplasia (Stafberg et al 1993). To our knowledge there are no clinical studies in transplanted patients with heparinlike substances presented as yet.…”