Post-transplant lymphoproliferative disorder (PTLD) is a serious complication typically associated with uncontrolled expansion of EBV+ B-cell clones following institution of immunosuppressive therapy (IST). Why PTLD develops in some transplant recipients but not in others remains unclear, although patient age, allograft type, and intensity of IST are implicated as risk factors. Additional factors, including the genetic background of the host, are likely to play an important role in PTLD. Strong evidence implicates EBV-reactive cellular immunity and TH-1 cytokines like interferon gamma (IFN-gamma) as important factors to prevent EBV reactivation and to control PTLD. Poly-morphisms in cytokine genes can affect cytokine secretion and function, thus providing a compelling rationale to study known sequence polymorphisms in cytokine genes as possible risk factors for the development of PTLD. We hypothesize that genetic polymorphisms inherent to the immune capacity of transplant patients is a contributing factor in determining risk of PTLD. Preliminary data in a preclinical SCID mouse (hu-PBL-SCID) model of spontaneous human EBV+ lymphoproliferative disorder (EBV-LPD) and in a small number of PTLD patients suggest that a A/T single nucleotide polymorphism at base +874 of the IFN-g gene is linked to the development of PTLD and EBV-LPD in hu-PBL-SCID mice. To confirm these findings, we will perform a multi-center, retrospective study to assess the prevalence of the A/T +874 IFN-g genotype in PTLD patients, and compare it to that of matched, non-PTLD transplant controls (Specific Aim 1). We will also test the hypothesis that PBL of the A/A IFN-gamma genotype have fewer IFN-gamma producing CD8+ cells and/or lower overall IFN-g production in response to autologous EBV LCL stimulation, compared to the T/T genotype (Specific Aim 2). Our team consists of Drs. A. VanBuskirk (immunologist, cytokine genotyping), P. Porcu (adult PTLD/lymphoma clinician and researcher), T. Gross (pediatric PTLD/lymphoma clinician and researcher), A. Ferketich (epidemiology and statistics) and R. Baiocchi (physician scientist specializing in PTLD and hu-PBL-SCID mouse). Being able to identify patients at high risk for PTLD would be very beneficial in terms of treatment and prevention strategies. Our overall goal is to use this data as a springboard for R01 proposals to study the molecular epidemiology of PTLD and to perform prospective therapeutic clinical trials in PTLD patients.
