Abstract 16873: A Human Model of Antibody Mediated Arteriosclerosis And Atherosclerosis

Abstract

Animal models have suggested an association between antibodies (Ab), endothelial cells and the development of arteriosclerosis/atherosclerosis. Our aim was to study the relationship between allo-antibodies and vascular injury in a human model of kidney transplantation where patients Ab levels are monitored and protocol biopsies performed with careful examination of renal cortical arteries. This study included all acute kidney rejection episodes of all 2717 kidney transplantations performed in 2 centers and individualized 302 patients with biopsy-proven acute rejection. We found that among these rejections, 64 patients (22%) had evidence of vascular rejection with donor-specific anti-HLA antibodies, characterized by intimal arteritis with monocytes/macrophages infiltrating the endothelium of arteries. Vascular rejection with antibodies progressed to more severe arteriosclerosis lesions at 1 year post-transplantation as compared to rejection without arteritis (p<0.01). Vascular rejection with anti-HLA antibodies and high grade arteritis showed lipid accumulation in arteries that was not observed in rejections without Ab. Vascular rejection with Ab was associated with the highest risk of graft loss (Hazard Ratio [HR]=9.7 vs T cell mediated rejection, p<0.01). Among the determinants of vascular rejection prognosis, the multivariate analysis demonstrated that high level of allo-antibodies (HR=3.8, p=0.029) was associated with a bad graft outcome whereas the use of antibody targeting strategy (steroids/Plasma-exchange/anti-CD20) was independently associated with improved graft prognosis (HR=0.19 vs steroids±[OKT3/Thymoglobulin], p<0.03). In conclusion, we used here a population of kidney transplantation as a unique human model to study the effects of antibodies in vessels. Using a large cohort of patients with biopsy proven rejections, we identified a new entity of antibody-mediated arteritis that promotes acceleration of arteriosclerosis and atherosclerosis. This model may provide new insights to the pathophysiology and the therapeutic options of arteriosclerosis and atherosclerosis diseases.