Donor cytokine genotype influences the development of acute rejection after renal transplantation

Background. Acute allograft rejection remains an important cause of morbidi ty after kidney transplantation, and has been shown to be a crucial determi nant of long-term graft function. Although rejection is mediated by recipie nt lymphocytes, both donor and recipient factors contribute to the local en vironment that influences the nature, severity, and duration of the rejecti on response. Cytokines are a major determinant of this milieu, and this stu dy sought to explore the impact of donor cytokine and cytokine receptor gen e polymorphisms on acute rejection after renal transplantation. Methods. A total of 145 cadaveric renal allograft donors were selected for analysis according to the presence or absence of graft rejection in the fir st 30 days after transplantation. DNA was genotyped for 20 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reactio n with sequence specific primers. Associations were assessed using continge ncy table analysis and the chi (2) test, using a two-set design. Results. A polymorphism at position -174 of the donor IL-6 gene was associa ted with the incidence (P=0.0002) and severity (P=0.000007) of recipient ac ute rejection. This finding was independent of HLA-DR matching. Acute rejec tion was not influenced by recipient IL-6 genotype, or by donor-recipient m atching of IL-6 genotype. Conclusion. This study identifies donor IL-6 genotype as a major genetic ri sk factor for the development of acute rejection after renal transplantatio n. This provides evidence that donor-derived cytokines play a major role in determining outcome after transplantation, and will contribute to the deve lopment of therapeutic algorithms to predict individuals at particularly hi gh risk of acute rejection.