Complement 5a Receptor Inhibition Improves Renal Allograft Survival

Abstract

Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.

Complement—here, there and everywhere, but what about the transplanted organ?

“…Other studies suggest antiapoptotic proteins such as BCL-2 and haem oxygenase 1 (HO1) upregulate CD55 thereby enhancing endothelial resistance and promoting accommodation of the graft [111]. ECs also modulate T cell function and expansion through local production of complement and CD88 signalling on T cells seen in heart and kidney transplantation models [112,113]. In view of this, manipulation of complement regulators may prove an effective treatment strategy in the treatment of antibody-mediated rejection.…”

Complement Receptors in Inflammation

“…Similarly, inhibition of C5aR in murine model of renal allotransplantation substantially improved graft survival from 11 days to 12 weeks. In addition, C5aR inhibition reduces kidney inflammation, apoptosis, and priming of alloreactive T cells (Gueler et al, 2008). Pharmacological targeting of C5aR during organ preservation significantly improves kidney graft survival (Lewis et al, 2008).…”

Should Complement Activation Be a Target for Therapy in Renal Transplantation?

“…In this issue of the JASN, Gueler et al 4 use human biopsy tissue and a mouse model to assess the role of C5a in renal transplantation. The receptor for C5a is expressed on macrophages and neutrophils infiltrating the graft as well as some tubular and glomerular cells.…”

“…9 Alternatively, C5a could be involved in other pathways that lead to graft injury, and of particular interest is its potential to augment the alloimmune response. In the report by Gueler et al 4 blocking the C5a receptor prevents graft rejection and reduces the recipient's response to donor in a mixed lymphocyte reaction. This could be due to nonspecific effect of C5a on tissue injury in the reperfusion phase.…”

“…13 This is a significant effect and is sufficient to modify the survival of murine cardiac allografts. 14 In the study by Gueler et al, 4 blocking C5a receptor signaling at a time when an allo-specific T cell response is developing is sufficient to prevent later rejection. The mechanism by which T cell reactivity remains suppressed is not known.…”