- Dr. Anne M. VanBuskirk, Principal Investigator
- Ms. Julie Dierksheide, Research Associate
- Ohio State University, Columbus, USA
- Cytokine Inhibition of CTL Reactivation and Post-Transplant Lymphoproliferative Disorder
Post-transplant lymphoproliferative disorder (PTLD) is an aggressive B cell malignancy afflicting approximately 2-7% of all transplant patients, with 50-90% mortality. Most PTLDs are B cell lymphomas associated with Epstein-Barr virus (EBV). Primary EBV infection and viral load in the post-transplant period are significant risk factors, but many aspects of PTLD remain poorly defined. Most adults harbor a latent EBV infection controlled by EBV-reactive cellular immune responses, which also prevent PTLD. However, immunosuppressive therapy necessary to prevent graft rejection results in defective immune surveillance, including a drop in EBV-specific CTL activity. The precise mechanism(s) by which the anti-EBV immune response fails is not clear, nor is it clear why only some transplant patients develop PTLD, although immune factors are thought to be important. One key mediator is IFNg, which contains an AàT polymorphism at residue 847. The T allele is associated with high cytokine production. We recently reported that the A/A genotype for IFNg is expressed more frequently in PTLD than in non-PTLD patients, and have now confirmed that observation using the SCID-Hu PBL mouse model. These data suggest that low IFNg is a factor in PTLD. Exciting preliminary data indicate that the A allele of the IFNg genotype is associated with an ability of TGFβ to inhibit CTL activity. Exogenous IFNg can overcome this inhibition. We also have data that indicate the inhibition occurs via the APC. We therefore hypothesize that TGFβ induced by immunosuppressive therapy inhibits EBV CTL in PBL with the A/A, but not the T/T, IFNg genotype, by altering APC function. We are uniquely able to investigate TGFβ-mediated CTL inhibition due to our bank of genotyped PBL donors and HLA-matched tumor cells. These PBL and matched tumor lines will be used to characterize the TGFβ-mediated inhibition and begin to dissect its mechanism. These results will increase our understanding of PTLD by addressing mechanisms of CTL inhibition by TGFβ and the association of CTL inhibition with cytokine genotype. These results may also provide information on potential therapeutic targets to treat or prevent PTLD.