Cytokine gene polymorphisms predict acute graft rejection following renal transplantation

Background. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-a lpha) has been implicated in the pathogenesis of acute rejection. while ani mal models suggest a role for interleukin-10 (IL-10) in promoting graft sur vival. It has also been shown that polymorphisms in the TNFA gene promoter (position -308) and in the IL-10 gene promoter (position -1082) correlate w ith differential production of these cytokines in vitro. The aim of this st udy was to determine whether TNF-alpha and IL-10 gene polymorphisms influen ce the incidence and severity of acute rejection in the first six months fo llowing renal transplantation. Methods. The cytokine genotypes of 115 consecutive first cadaveric kidney a llograft recipients and their donors were screened. The rejection episodes (REs) were defined clinically and confirmed histologically where possible a nd further classified according to severity (RS), namely steroid-resistant or responsive REs. The genotypes were then correlated with the REs and RS. Results. The recipient TNF-alpha high producer genotype and IL-10 high prod ucer genotype were significantly associated with multiple REs (greater than or equal to 2) in human leukocyte antigen (HLA)-DR mismatched transplants (P = 0.0047 and P = 0.045, respectively), whereas only the TNF-alpha high p roducer genotype was associated with steroid-resistant REs (P = 0.025). Whe n recipient cytokines were analyzed together, the TNF-alpha high/IL-10 high producer genotype had the worst prognosis, whereas TNF-alpha low/IL-10 low producer genotype was protective. Conclusions. We conclude that recipient TNF-alpha and IL-10 gene polymorphi sms are determinants of REs and RS following kidney transplantation. Routin e screening of these gene polymorphisms may have a clinical role in identif ying patients at risk of multiple REs and severe rejections.