Kinetics and Characteristics of Monocyte Subsets in Kidney Transplant Recipients

Abstract

Although a major contribution of monocyte-macrophage cell lineage to kidney graft rejection and injury has been documented, it is unclear how the monocyte-macrophage related responses develop after kidney transplantation. Macrophages are present in large numbers in acutely rejecting grafts. Monocyte accumulation in peritubular capillaries is one of the main features of acute humoral rejection. The correlates of innate immunity to graft rejection and survival remain to be elucidated. Here, we analyzed the kinetics and characteristics of peripheral blood monocyte subsets after kidney transplantation. By flow cytometry the phenotypic characteristics of classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes were measured. To study the activation status, cell surface expression of co-stimulatory molecules CD40 and CD80 and MHC class II molecule HLA-DR was determined. Whole blood analysis was performed in a cohort of 30 healthy individuals, 30 renal transplant recipients at the time of transplantation, 17 recipients at 3 months, and 16 recipients at 6 months after transplantation in a cross-sectional approach. Our data reveal that, as a sign of triggered innate immunity, the percentage of CD14/16+ intermediate-non classical proinflammatory monocytes was significantly increased at the time of transplantation compared to healthy individuals (22.3% ± 2.3 and 15.1% ± 0.9 respectively; p≤0.001). Remarkably, despite potent immunosuppressive drugs, this increase in proinflammatory monocytes, and the concomitant decrease in the classical subset (69.3% ± 3.4 and 74.9% ± 1.5 respectively; p≤0.001) was retained during the post transplant course when the kidney function was recovered. Although the percentage of CD40 and CD80 expressing monocytes and the level of cell surface expression of CD40, CD80 and HLA-DR within the different monocyte subsets did not differ between kidney transplant recipients and healthy individuals, the percentage of HLA-DR expressing monocytes was significantly increased at the time of transplantation. This reached a minimum at 3 months and was followed by a recovery towards normal range after 6 months. In conclusion, in kidney transplant recipients the balance in monocyte subsets is skewed towards intermediate and non-classical subsets. This shift could be one of major cellular drivers of early post-transplant immunity that may determine the outcome of kidney transplant.