Beneficial Immune Effects of Myeloid-Related Proteins in Kidney Transplant Rejection

Abstract

Acute rejection is a risk factor for inferior long-term kidney transplant survival. Although T cell immunity is considered the main effector in clinical acute rejection, the role of myeloid cells is less clear. Expression of S100 calcium-binding protein A8 (S100A8) and S100A9 was evaluated in 303 biopsies before and after transplantation from 190 patients. In two independent cohorts of patients with acute rejection (n = 98 and n = 11; mostly cellular rejections), high expression of S100 calcium-binding protein A8 (S100A8) and A9 (S100A9) was related to improved graft outcome. Mechanisms of action of the S100 molecules were investigated. In the graft and peripheral blood cells, S100A8 and S100A9 expression correlated with myeloid-derived suppressor markers. In line with this finding, recombinant S100A8 and S100A9 proteins inhibited maturation and the allogeneic T cell stimulatory capacity of dendritic cells. S100A9 enhanced the production of reactive oxygen species by macrophages, which suppressed T cell activity at low concentrations in the form of hydrogen peroxide. Intragraft S100A8 and S100A9 expression linked to reduced expression of T cell immunity and tissue injury markers and higher expression of immune regulatory molecules. This study sheds new light on the importance of myeloid cell subsets in directing the outcome of T cellmediated acute rejection.

S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy

“…Supporting this study, Rekers et al . showed that high levels of S100A8/A9 correlated with improved graft outcome after kidney transplantation . Thus, we hypothesized that S100A8/A9 would dampen macrophage‐induced inflammation and the development of renal fibrosis following UUO.…”

“…S100A8/A9 is a critical player during inflammatory responses . Previous studies have shown that, in human diseases, S100A8/A9 can be detected in serum, aspirates or faeces of patients with rheumatoid arthritis , acute rejection , inflammatory bowel disease , lung disease , systemic sclerosis and atherosclerosis . In the context of renal fibrosis, we are the first to show that S100A8/A9 expression is increased in patients with obstructive nephropathy and localizes uniquely to interstitial granulocytes and not to other parenchymal cells, such as epithelial cells .…”

Immunological biomarkers of tolerance in human kidney transplantation: An updated literature review

“…Expressions of human S100 calcium‐binding protein A8 and S100 calcium‐binding protein A9, which suppress immune responses, in the graft and PBMCs, are related to MDSCs marker and improved graft outcome. Rekers et al () indicated that S100 A8 and A9 proteins significantly increased during posttransplant phase versus a pretransplant period in the patients with stable graft function, but the differences were not significant in the patients with acute rejection. They also demonstrated that patients with acute rejection, expressing high levels of S100A9 mRNA, had better graft function for at least 6 years compared with patients with acute rejection, expressing decreased S100 A9 mRNA (Rekers et al, ).…”

Calcium-Binding Proteins S100A8 and S100A9: Investigation of Their Immune Regulatory Effect in Myeloid Cells

“…The role of myeloid cells in allograft rejection has been increasingly appreciated [ 17 , 18 , 19 ]. We found in human kidney transplants that acute rejection episodes with high tissue expression of S100A8 and S100A9 have a more favorable long-term outcome than rejections with low expression [ 20 , 21 ], suggesting that the S100 proteins exert beneficial immune effects. Double immunofluorescence on tissue biopsies showed that S100A9 largely co-localized with CD68 and HLA-DR, but that only a minority of S100A9+ cells expressed the macrophage type 2 marker CD163.…”