PREDICTIVE VALUE OF CYTOKINE GENOTYPING FOR THE RISK OF POST TRANSPLANT LYMPHOPROLIFERATIVE DISEASE IN SOLID ORGAN TRANSPLANT RECIPIENTS.
A Zeevi, D Green, D Row, M Ahmed, C Sturchio, J Martell, M Awaad, J Reyes, G Mazariegos, M Nalesnik and S Webber, Thomas E Starzl Transplant Institute and Childrens Hospital, University of Pittsburgh, Pittsburgh, PA.
Post Transplant Lymphoproliferative Disorder (PTLD) refers to a range of hyperplastic to neoplastic lymphoid proliferation, which develops post transplantation and most often are of B cell origin. The primary Epstein Barr Virus (EBV) infection following transplantation was associated with 10% PTLD in pediatric patients and with 5% frequency in adults. There is a marked variation of incidence of PTLD (1-23%) in different transplanted organs, which relates to the dose and intensity of immunosuppression. Clinical studies with patients with PTLD suggested the presence of Th-2 cytokine environment both systemically and in the lesion. Since cytokine play an important role in the host’s immune response to EBV infection, genetic predisposition of Th1 or Th2- like cytokines may contribute to the risk of PTLD. Polymorphism have been described for many cytokine and cytokine receptor genes. We tested the gene frequency for pro-inflammatory cytokines IFN- and TNF- and for regulatory cytokines IL-6, IL-10, TGF- and for IL-4 receptor mutant using SSP-PCR methodology (One Lambda, Inc). We analyzed cytokine polymorphism in 49 pediatric recipients including 15 with PTLD and in 15 adult transplant recipients (10 with PTLD). In pediatric patients with PTLD the frequency of IFN- low was 42% (5/12) in comparison to 12% (2/16) in non-PTLD patients. Furthermore in adults 8/10 patients with PTLD expressed IFN- low genotype. Overall the IFN-low genotype was significantly associated (p<0.005) with PTLD in patients with primary EBV infection (sensitivity 59%, specificity 81%). The majority (16/17, 94%) of PTLD patients also exhibited IL-6 high genotype while only 72% of non-PTLD patients had IL-6 high genotype. IL-10 high and TNF-low genotypes seem to be enriched in patients with PTLD. TGF-and IL4-receptor mutant genotypes were equally distributed in PTLD and non-PTLD patients. The chronic high EB viral load carrier status was associated with IFN- low genotype. Our pilot data suggest that in patients at risk for PTLD low IFN-and high IL-6 genotoype may constitute additional risk factors for the development of PTLD. Cytokine genotype may also influence long-term ability to control EB viral load in transplant recipients.