Background. Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. Although rejection is mediated by recipient lymphocytes, both donor and recipient factors contribute to the local environment that influences the nature, severity, and duration of the rejection response. Cytokines are a major determinant of this milieu, and this study sought to explore the impact of donor cytokine and cytokine receptor gene 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 first 30 days after transplantation. DNA was genotyped for 20 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reaction with sequence specific primers. Associations were assessed using contingency table analysis and the χ2 test, using a two-set design.
Results. A polymorphism at position −174 of the donor IL-6 gene was associated with the incidence (P =0.0002) and severity (P =0.000007) of recipient acute rejection. This finding was independent of HLA-DR matching. Acute rejection was not influenced by recipient IL-6 genotype, or by donor-recipient matching of IL-6 genotype.
Conclusion. This study identifies donor IL-6 genotype as a major genetic risk factor for the development of acute rejection after renal transplantation. This provides evidence that donor-derived cytokines play a major role in determining outcome after transplantation, and will contribute to the development of therapeutic algorithms to predict individuals at particularly high risk of acute rejection.
Oxford Transplant Centre, Nuffield Department of Surgery, Oxford Radcliffe Hospitals, Oxford, OX3 7LJ, UK
1 Address correspondence to: Sara E. Marshall, MRCP, MRCPath, PhD, Oxford Transplant Centre, Nuffield Department of Surgery, Oxford Radcliffe Hospitals, Oxford, OX3 7LJ, UK.
2 Funded by a Clinician Scientist Fellowship from the Medical Research Council, UK.
Received 14 March 2000.
Accepted 24 April 2000.