Development Of Allograft Arteriosclerosis Research Articles

Post Transplant DSA: Independent Factor of Accelerated Arteriosclerosis in Kidney Transplant Population.

Background Animal models and previous reports have suggested a role for anti-HLA antibodies in the development of allograft arteriosclerosis. Our aim was to use an epidemiologic approach to model the respective non-immune and immune parameters associated with development of early arteriosclerosis post transplantation. Methods We included kidney recipients (2004-2010) having evaluation of arteriosclerosis on kidney biopsies performed at 1-year post-transplant (n=744). We assessed the determinants of severe arteriosclerosis (cv Banff score ≥2) using exhaustive evaluation of donor and recipient characteristics, traditional cardiovascular factors and immunological profile in the first year post transplant. Results Two distinct populations were identified according to allograft arteriosclerosis lesions identified at 1-year post transplantation: 1) patients with minimal arteriosclerosis (n=494); 2) patients with severe arteriosclerosis (n=250). As compared to patients with minimal arteriosclerosis, patients with severe arteriosclerosis were significantly older (45±12 vs 52±12, p<0.0001), received older donors (47±16 vs 58±13, p<0.0001) with increased rate of death by cerebrovascular disease (p<0.001), increased cold ischemia time (p<0.0001) and were more sensitized at the time of transplantation. Patients with severe arteriosclerosis and DSA had lower 8 years graft survival as compared to severe arteriosclerosis without DSA (p<0.001). The determinants ofsevere arteriosclerosis at 1 year were i) donor cardiovascular factors: age, male gender, hypertension, diabetes mellitus and dyslipidemia ii) Recipient age, Post transplant recipient systolic blood pressure, diabetes mellitus, LDL blood level iii) rejection episodes and presence of circulating DSA. In the multivariate Cox model, the factors independently associated with severe arteriosclerosis at 1 year post transplantation were: donor age (HR 1.048, p<0.0001), male donor gender (HR 1.048, p<0.0001), Recipient age (HR 1.021, p<0.0185), recipient diabetes post-transplant (HR 3.751, p<0.0042) and the presence of DSA (HR 3.262, p<0.0001). The results were replicated in an independent validation sample of 321 kidney recipients. Conclusion We defined in a large cohort a kidney transplant recipients the independent non-immune and immune determinants of accelerated arteriosclerosis post transplantation with independent association with DSA post transplant.

Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis.

Angiopoietin (Ang)-1 is an angiogenic growth factor that counteracts the permeability and proinflammatory effects of vascular endothelial growth factor and other proinflammatory cytokines. Recently, we demonstrated that vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Here, we studied the roles of Ang1, its natural antagonist Ang2, and their receptor Tie2 in rat cardiac allograft arteriosclerosis. Heterotopic cardiac allografts and syngrafts were transplanted from Dark Agouti (DA) to Wistar-Furth rats and from DA to DA rats, respectively. Immunohistochemistry disclosed that only a few mesenchymal cells expressed Ang1 in normal hearts and syngrafts, whereas no immunoreactivity was found in cardiac allografts undergoing chronic rejection. Ang2 and Tie2 immunoreactivity was induced mainly in capillaries and postcapillary venules in chronic allografts when compared with syngeneic controls, but no immunoreactivity was found in arterial endothelium. Intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector encoding human Ang1 (Ad.Ang1) protected against the development of allograft arteriosclerosis. Ad.Ang1 perfusion reduced Ang2 expression in microcirculation, the numbers of graft-infiltrating leukocytes, and the level of immunoactivation and interstitial fibrosis, as well as both the incidence and intensity of intimal lesions. Ad.Ang1 perfusion also increased CD34+ stem cell counts in peripheral blood. Our findings suggest that the antiinflammatory properties of Ang1 may offer an entirely new therapeutic approach to prevent cardiac allograft arteriosclerosis.

Mouse model of transplant arteriosclerosis: role of intercellular adhesion molecule-1.

Transplant-accelerated arteriosclerosis in coronary arteries is the major limitation to long-term survival of patients with heart transplantation. The pathogenesis of this disease is not fully understood. Herein, we describe a simplified model of artery allografts in the mouse that allows us to take advantage of transgenic, knockout, or mutant animals. Common carotid arteries or aortic vessels were end-to-end allografted into carotid arteries between C57BL/6J and BALB/c mice. Neointimal lesions were observed as early as 2 weeks after surgery and had progressed at 4 and 6 weeks postoperatively. The lumen of grafted arteries was significantly narrowed due to neointima hyperplasia 4 weeks after transplantation. Using this model, we studied the role of intercellular adhesion molecule-1 (ICAM-1) in the development of transplant arteriosclerosis in ICAM-1-deficient mice. Neointimal lesions of artery grafts from ICAM-1 -/- C57BL/6J to BALB/c mice were reduced up to 60% compared with wild-type controls. MAC-1 (CD11b/18)-positive cells adhering to the surface of ICAM-1 -/- artery grafts were significantly less as identified by en face immunofluorescence, and these positive cells were more abundant in intimal lesions of artery grafts in wild-type mice. Furthermore, the major cell component of neointimal lesions 4 weeks after surgery was found to be alpha-actin-positive smooth muscle cells, which were significantly reduced in lesions of ICAM-1 -/- artery grafts. Thus, this model has been proven to be useful for understanding the mechanism of transplant arteriosclerosis. Our findings demonstrate that ICAM-1 is critical in the development of allograft arteriosclerosis via mediation of leukocyte adhesion to, and infiltration into, the vessel wall.