A GENETIC-MARKER OF HIGH TNF-ALPHA PRODUCTION IN HEART-TRANSPLANT RECIPIENTS

The cytokine TNF-alpha has been implicated in the pathogenesis of both acute and chronic transplant rejection. Levels of the cytokine are kn own to vary in a normal population, leading to speculation that high r esponders may be at greater risk of rejection. Particular TNF region p olymorphic markers have been associated with increased TNF-alpha level s and a biallelic polymorphism has been identified at position -308 of the TNF-alpha promoter that may contribute significantly to the inter individual variation in healthy persons. We describe here a new associ ation between a polymorphic locus in the TNF gene region and increased production of TNF-alpha in heart transplant recipients. We studied tw o microsatellite markers that flank the TNFA gene, as well as a bialle lic polymorphism at position -308 of the TNFA promoter, and found that the microsatellite allele TNFd3 was significantly associated with the capacity of leukocytes to produce TNF-alpha in vitro. No association was demonstrated for the promoter region polymorphism. Patients were r eceiving cyclosporine (CsA) and prednisolone (pred) at the time of sam pling, which are known to interrupt 5' regulation of TNFA transcriptio n in T cells and macrophages and may therefore negate the influence of the -308 polymorphism. Because of this we suggest that TNFd3 may be a marker for a 3' repressor region polymorphism that is of importance i n immunosuppressed individuals.