FcγRIIIb Inhibits Renal Transplant Rejection by Inducing Neutrophils Apoptosis

Abstract

Fcγ receptors (FcI³R) have been proposed to be involved in the pathogenesis of acute rejection (AR) after organ transplantation. However, the mechanisms by which FcγRIIIB mediate this process are still unclear. Previous studies suggested that the FCGR3B gene copy number variation (CNV) is associated with the risk of autoimmune diseases. In this study, we delineated the association of FCGR3B-CNV with end-stage renal disease (ESRD) and risk of rejection post kidney transplantation in 414 kidney transplant recipients and 219 healthy subjects. Our data showed that the percentage of kidney transplant recipients with high copy number of FCGR3B gene was significantly lower than that of healthy controls, suggesting that individuals with low copy of FCGR3B gene are more prone to develop ESRD. Besides, patients with low copy of the FCGR3B gene are associated with susceptibility to AR following kidney transplantation. In mice, transgenic expression of human FcγRIIIB effectively inhibited the AR and improved the function of the transplanted kidney in a model of allogeneic kidney transplantation. This protective effect was associated with an inhibition of T lymphocytes infiltration and Th1 cell immune response. Finally, we showed that FcγRIIIB cross-linking combined with TNF-α treatment in vitro promoted neutrophil apoptosis and was associated with increased activation of cleaved caspase-8 and caspase-3. The combined treatment also increased the arginase-1 expression in neutrophils, which may explain FcγRIIIB-mediated immunosuppression. Funding: This work was supported by the National Fund Committee of China (2012CB517603, 2012AA02A512). Declaration of Interest: No conflicts of interest exist for any authors. Ethical Approval: The study was performed in adherence with the Declaration of Helsinki, and was approved by the Ethics Committee of the First Affiliated Hospital of College of Medicine of Zhejiang University. All patients and healthy controls provided written informed consent.