Don Constantino

TNF-α, IL-6, IFN-γ, and IL-10 gene expression polymorphisms and the IL-4 receptor α-chain variant Q576R: Effects on renal allograft outcome

BACKGROUND There has been much interest recently in the effects of various cytokine gene expression polymorphisms on graft outcome. However, the results of these investigations reveal the outcomes to be organ-specific and center-specific. We sought to confirm and add to some of the earlier findings by studying the impact of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) polymorphisms and the interleukin-4 (IL-4) receptor alpha-chain variant on posttransplant renal allograft outcome. METHOD TNF-alpha, IL-6, IFN-gamma, and IL-10 gene promoter region polymorphisms were assayed genotypically by PCR-SSP on 120 patients transplanted at the Albany Medical Center. These patients were also typed for the IL-4 receptor alpha-chain variant Q576R. RESULTS Producers of high levels of the proinflammatory cytokine TNF-alpha were found to be at increased risk for acute rejection episodes if the allograft was mismatched for the molecular products of the class II region of the human major histocompatibility complex (HLA-DR). Expression level polymorphisms of the IL-6, IFN-gamma, and IL-10 genes were not associated with acute rejection episodes, nor was the IL-4 receptor alpha-chain variant Q576R. CONCLUSIONS These data would suggest that the production of high levels of the cytokine TNF-alpha is especially detrimental to graft survival when the recipients T-helper lymphocytes are being activated by mismatched donor HLA-class II antigens. Typing all potential kidney recipients for TNF-alpha, and providing well-matched organs for high producers of this cytokines, may be expected to increase rejection-free graft survival in these patients.

The new kidney allocation system does not equally advantage all very high cPRA candidates – A single center analysis

The new UNOS kidney allocation system awards very high points to candidates with cPRA 99% and 100%, and allows for national sharing for cPRA 100% candidates. We sought to determine the effect of this new kidney allocation system on candidates who are very highly sensitized (90-98% cPRA) but not eligible for very high points or national sharing by examining offers to these candidates for 5months pre-implementation and two consecutive 5month periods post-implementation and comparing them to cPRA⩾99% candidates. We found that the cPRA⩾99% candidates received significantly more offers and transplants after implementation, while offers and transplants to the 90-98% candidates decreased. A slight adjustment to the allocation system may be needed to provide more equitable distribution of kidneys to all high cPRA candidates.

Promoter-region alleles of the TNF-alpha and IL-10 genes have no effect on pretransplant alloantibody production.

BACKGROUND The presence of high levels of alloantibodies are known to be a risk factor in renal graft outcome. Expression level polymorphisms in cytokine genes are also thought to have an effect on allograft outcome, but the studies examining this have been inconsistent. This may be due to center-specific differences in immunosuppressive protocols. Therefore, we studied the effects of these polymorphisms on pretransplant class I alloantibody production in nonexogenously immunosuppressed candidates. METHODS Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) gene polymorphisms were assayed genotypically by PCR-SSP on 177 renal transplant candidates. Candidates with a peak goat antihuman immunoglobulin-enhanced T-cell panel reactive antibody (PRA) of >or=10% were considered to be positive for alloantibody (32% of 177 total). RESULTS Previous transplants, transfusions, or pregnancies were all associated with alloantibody production, but TNF-alpha and IL-10 phenotypes were not. High levels of alloantibody production (peak PRA >50%) were also not effected by cytokine phenotype. CONCLUSIONS These data suggest that differences in TNF-alpha and IL-10 phenotype do not effect a patients likelihood of becoming sensitized by transfusions, pregnancies, and prior transplants.