Effect of cytokines and chemokines (TGF-beta, TNF-alpha, IL-6, IL-10, MCP-1, RANTES) gene polymorphisms in kidney recipients on posttransplantation outcome: influence of donor-recipient match

Posttransplantation alloantigen-dependent and alloantigen-independent processes are both mediated by cytokines and chemokines. Recently cytokines and chemokines, as well as their receptors, have been shown to be highly polymorphic. The cytokine and chemokine gene polymorphisms are associated with variable production, activity, expression, or ligand-receptor affinity. The aim of our study was to analyze the relation between selected cytokine and chemokine gene polymorphisms in kidney donors and recipients as a function of donor-recipient match and posttransplantation outcome. Polymorphisms transforming growth factor-beta (TGF-beta); tumor necrosis factor-alpha (TNF-alpha); interleukin (IL)-6, and IL-10; monocyte chemoattractant protein-1 (MCP-1); and RANTES (regulated upon activation, normal T-cell expressed and secreted) genes were determined using DNA Polymerase chain reaction technology in 268 healthy volunteers, 345 kidney transplant recipients (1997 to 1999), and 298 cadaveric donors. Patients were followed up for 4 to 6 years. The distribution of alleles of selected genes was identical in control subjects, cadaveric donors, and recipients. Low TGF-beta production in both the donor and recipient genotypes was associated with risk for early rejection (6 months) and worse graft function at 4 years. The only tendency for worse graft outcome was observed among donor-recipient combinations mismatched for TGF-beta genotype. Genetic determination of TNF-alpha and IL-10 production was associated with delayed graft function and rejection. IL-6 gene polymorphisms had no effect on the incidence of early acute rejections, but was associated with worse 5-year outcomes. Determinations of MCP-1 overproduction and RANTES-109 TT allele were associated with significant deterioration of graft function. Our data support the hypothesis that the strength of the alloimmune response after transplantation is in part genetically determined. Donor-recipient matching of cytokine gene polymorphisms has a marginal effect.