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Pre‐transplant serum level of CXCL9 as a biomarker of acute rejection and graft failure risk in kidney transplantation

Kidney transplantation is the reference treatment for patients with end-stage renal disease. The advent of this therapeutic option has notably enhanced survival in patients with this disease. Nevertheless, morbidity and mortality remain much higher in transplant recipients than in the general population. Thus, today, effort has to be made to find more efficient treatments and to improve diagnosis. Moreover, there is a need to identify factors predictive of long-term graft outcome that could promote the implementation of a more personalized form of medicine. Chemokines are a group of small molecules that are known for their effect on cell trafficking. They also play fundamental roles in the development, homeostasis and function of the immune system [1,2]. They are divided into two major subfamilies, CXC and CC, based on the arrangement of two conserved cysteine residues separated by a single amino acid in CXC chemokines and adjacent in CC chemokines. Among them, CXCL9, CXCL10 and CXCL11 are T-cell and NK-cell chemoattractant molecules that have been shown to be abundant in the graft and to be regulated by interferon-c. These chemokines are able to mediate pleiotrophic biologic functions. They are ligands of the CXCR3 molecule expressed by effector T cells infiltrating the allograft and have also been detected in biopsies with acute rejection [3,4]. Today, the exact role of CXCR3 and its ligands in organ transplantation remains unknown. MHC mismatched CXCR3 mouse recipients were shown to experience prolonged cardiac allograft survival for several weeks and even long-term survival when additionally treated with low doses of CsA for a few days [3]. These data provide new insight into CXCR3 and chemokine receptors as potential targets for novel therapeutic strategies in transplantation. Nevertheless, such results were not confirmed in fully mismatched allografts [5]. Moreover, Kwun et al. evaluated the effect of the CXCR3 receptor antagonist MLR-957 on cardiac allograft survival and of the antiCXCR3 mAb in human CXCR3 knock-in mice and reported only a moderate increase in graft survival. He consequently concluded on a weak role of CXCR3 in allograft rejection and on a modest contribution of CXCR3 to leukocyte trafficking [6]. Thus, to date, the relevance of such a molecule and its ligands in human transplantation is still largely debatable [7]. Nevertheless, the question remains as to why CRCR3 as well as its ligands, CXCL9, CXCL10 and CXCL11, are so abundant in biopsies from patients with acute rejection. In their paper in this issue of Transplant International, Rotondi et al. did not question the mechanisms or involvement of chemokines and their ligands in organ transplantation, but retrospectively measured CXCL9 levels in pre-transplant serum samples collected from 252 kidney graft recipients. They reported that combined measurement of both pre-transplant CXCL9 and CXCL10 serum levels might represent a clinically useful parameter to identify subjects at high risk of acute rejection and graft failure. Why patients under standard or peritoneal dialysis have much higher CXCL9 levels than normal individuals is puzzling and comparison with values in Correspondence Sophie Brouard, ITERT, INSERM U643, 30 Bd Jean Monnet, Nantes 44093, France. E-mail: Sophie.Brouard@univ-nantes.fr