Influence of the FcγRIIIa genetic polymorphism on the effect of antithymocyte globulins on lymphocyte populations in kidney transplantation
David Ternant, Matthias Büchler, Gilles Thibault, Mélanie Wilbaux, Azmi Al Najjar, Hervé Watier, Yvon Lebranchu, Gilles Paintaud
Tours university hospital, Tours, France.
Objectives: Polyclonal antilymphocyte globulins (ALG) have been used in transplantation for several decades but the sources of the interindividual variability of their effect are poorly understood. In vitro, ALG induce T lymphocyte depletion by apoptosis or by antibody-dependent cellular cytotoxicity (ADCC). We previously showed that polymorphism of FCGR3A, the gene that encodes FcγRIIIa receptor involved in ADCC, influences the relationship between horse ALG (h-ALG, Lymphoglobuline®) concentration and lymphocyte depletion in kidney transplanted patients [1]. The objective of this study was to confirm the influence of the FCGR3A genotype on the biological response to ALG treatment, using data from patients treated by rabbit ALG (r-ALG).
Methods: Among 194 patients kidney transplanted between 1998 and 2002 and treated with r-ALG (Thymoglobuline®), 69 were eligible and actually included in the study. Total lymphocyte count was used as a biomarker of effect and was followed until one year after the beginning of r-ALG treatment. All patients were genotyped for FCGR3A-158V/F polymorphism. Dose-effect data were analyzed using an indirect response model with inhibition of lymphocyte input. Since r-ALG concentrations were not available, a K-PD model was developed. The kin and kout parameters were lymphocyte input and output constants, R0 was the difference between initial and remote lymphocyte count, and EDK50 was the virtual infusion rate leading to 50% of lymphocyte depletion. A population approach was used. The influence of age, weight, concomitant immunosuppressive treatment and FCGR3A polymorphism on K-PD parameters was investigated.
Results: Lymphocyte count data were satisfactorily described using the K-PD model. Typical values (and interindividual CV%) were: kin = 1750 mm-3h-1 (16.3%), kout = 2.8 h-1, R0 = 860 mm-3. Patients with V allele were more sensitive to r-ALG treatment: EDK50 of FF, VF and VV patients were 0.35, 0.22 and 0.14 mg/h, respectively (p=5.1.10-4). In addition, kin was higher in patients co-treated with tacrolimus, and sensitivity to r-ALG treatment increased with age and body weight, and was higher in patients co-treated with sirolimus.
Conclusions: Our results confirm that FCGR3A genetic polymorphism influences r-ALG dose-effect relationship on lymphocyte count in kidney transplantation. This suggests that r-ALG act, at least in part, by ADCC.
References:
[1] Ternant D, Büchler M, Bénéton M, et al. Interindividual variability in the concentration-effect relationship of antilymphocyte globulins – a possible influence of FcgRIIIa genetic polymorphism. Br J Clin Pharmacol 2008; 1: 60–8.