Deficiency of C5aR Prolongs Renal Allograft Survival

Abstract

Interaction between C5a, a product of complement activation, and its receptor (C5aR) upregulates antigen-specific T cell responses by modulating the activation of antigen-presenting cells and T cells. Whether this C5a-C5aR interaction contributes to the immune responses that promote renal allograft rejection is unknown. Here, we found that deficiency of C5aR in both graft and recipient reduced allospecific T cell responses and prolonged renal allograft survival. In addition, lack of C5aR impaired the function of donor and recipient antigen-presenting cells and inhibited the response of recipient T cells to allostimulation. Furthermore, deficiency of C5aR in both graft and recipient reduced early inflammation in the grafts, with less cellular infiltration around the vessels and fewer F4/80 positive cells in the peritubular interstitium. These data demonstrate that C5aR is critical for a full adaptive immune response and mediates renal allograft rejection. Engagement of C5aR on dendritic cells and T cells modulates their function, enhancing allospecific T cell responses that lead to allograft rejection. Targeting C5a signaling may have therapeutic potential for T cell-mediated graft rejection.

Novel roles of complement in T effector cell regulation

“…Administration of an anti-C5 mAb that inhibits C5 cleavage synergized with CTLA4-Ig to prevent in vivo T cell priming and prolong heart transplant survival in mice . Finally, recently published work indicates that genetic deficiency of C5aR in the donor and in the recipient limits T cell alloreactivity and results in prolonged murine kidney allograft survival (Li et al 2010). Together these observations are consistent with the interpretation that complement is a physiologically important regulator of alloreactive T cell immunity.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Various complement components are involved in renal allograft damage and fibrosis (81)(82)(83). For example, complement promotes fibrosis and reduces allograft survival in proteinuric and non-proteinuric models of renal fibrosis and kidney transplantation (84)(85)(86)(87)(88)(89). Several clinical trials targeting the complement system are ongoing in various renal diseases, including renal allografts (81).…”

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

“…These results are consistent with findings reported by He et al 24 It is well established that C3a and C5a bind with high affinity to the C5a receptor (C5aR) on polymorphonuclear leukocytes, monocytes, and macrophages 29 to stimulate oxidative metabolism and the production of reactive oxygen species in neutrophils and T cells, thereby leading to the amplification of inflammatory responses. 65,66 It is worth noting that we did not have any primary reasons to select AST instead of ALT as a main parameter for the detection of the degree of liver injury in our experiments. It has been widely accepted that both AST and ALT are standard clinical and experimental biomarkers for monitoring the liver damage.…”