Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication often associated with Epstein-Barr virus (EBV). In healthy individuals, EBV-reactive memory responses prevent clinical symptoms of the life-long EBV infection. In PTLD, EBV-reactive memory responses, particularly CD8⁺ cytotoxic T lymphocyte (CTL) responses, are unable to control EBV lymphoproliferation and tumor formation. Based on our work and that of others, we hypothesize that IFN-g/TGF-ß interactions are important in determining if PTLD develops. It is well established that IFN-g and TGF-ß act antagonistically in immune responses and angiogenesis. We know that lymphoproliferative disease in hu-PBL SCID mice, an established model of PTLD, is associated with the low producer genotype for IFN-g (A/A at position +874). An A allele at position +874 is associated with the ability of TGF-ß to inhibit re-stimulation of EBV-reactive CTL in vitro. New data indicate that TGF-ß inhibits memory CTL restimulation via antigen-presenting cells (APC) and IFN-g can overcome the inhibition, suggesting that APC are important regulators of memory CTL restimulation. Neutralization of TGF-ß in hu PBL-SCID mice allows expansion of human CD8⁺ cells and reduced tumor incidence. While neutralizing TGF-ß protects hu PBL-SCID mice from LPD, the mechanism is unknown. We hypothesize that TGF-ß neutralization alters the cytokine balance to favor IFN-g, which counteracts TGF-ß, allowing effective CTL restimulation and reducing tumor angiogenesis. There are several predictions that follow from our hypothesis. First, IFN-g and inflammatory chemokines will be increased in the sera and tumors of anti-TGF-ß treated mice compared to controls. Second, tumors from anti-TGF-ß treated mice will have altered adhesion molecule profiles and reduced angiogenesis. Thirdly, T cells and APC from anti-TGF-ß treated mice will show hallmarks of increased IFN-g. Testing these predictions using in vitro and in vivo approaches will help define the mechanism by which TGF-ß neutralization prevents LPD in hu PBL-SCID mice. Understanding lymphomagenesis and its prevention will provide insights into how to prevent and treat clinical PTLD.