Beneficial Effects of High S100A9 Expression On Graft Infiltrating Myeloid Cells in Kidney Transplantation.

Abstract

Our goal is to predict the impact of acute rejection (AR) on kidney graft outcome using molecular markers. In patients suffering from AR (n=28) we initially identified by microarray S100A9 expression as a prognostic indicator of graft outcome. In a second cohort, we confirmed that patients with high S100A9 expression during AR (n=36) have significantly better 12-year graft survival (91.5%) than low expressers (n=61; 69.2%). Next, we studied the mechanism by which S100A9 exerts its biologic effects. In the biopsies, the S100A9+ cell population consisted of CD68+ myeloid cells of which 75% expressed HLA-DR. A minor fraction of S100A9+ cells represented CD66b+ granulocytes. S100A9 levels were related to expression of immune regulatory molecules IL-10, FoxP3/CD3, and p40 component of the reactive oxygen species (ROS)-producing machinery. Overexpression (10-35 fold) of S100A9 in cultured macrophages led to a dose-dependent increase in ROS production, whereas S100A9 inhibition by siRNA transfection resulted into decreased ROS production. The presence of low concentrations of the ROS metabolite H2O2 for 0.5h led to a significant downregulation of the proliferative response of activated T cells. S100A9 levels in the graft are specifically elevated during conditions of increased inflammation. The presence of distinct myeloid cell subsets early after transplantation provides prognostic information with respect to graft survival. The data suggest that an increased expression of S100A9 by myeloid cells leads to local ROS production in the immune synapse, and as a consequence, to downregulation of the alloimmune responses by T cells to the graft.