IFN-γ gene polymorphisms associate with development of EBV+ lymphoproliferative disease in hu PBL-SCID mice

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Abstract
Posttransplantation lymphoproliferative disorder (PTLD) is a devastating post-transplantation complication often associated with Epstein-Barr virus (EBV). Although the type and length of immunosuppression are risk factors, a patient's inherent immune capacity also likely contributes to this disorder. This report uses severe-combined immunodeficient mice given injections of human peripheral blood leukocytes (hu PBL-SCID [Severe Combined Immunodeficient] mice) to test the hypothesis that cytokine genotype associates with the development of EBV-associated lymphoproliferative disease (LPD). We observed that the A/A (adenosine/adenosine) genotype for base + 874 of the interferon γ (IFN-γ) gene was significantly more prevalent in PBLs producing rapid, high-penetrance LPD in hu PBL-SCID mice, compared to PBLs producing late, lowpenetrance LPD or no LPD. In examining the relationship between genotype and cytolytic T-lymphocyte (CTL) function, transforming growth factor β (TGF-β) inhibited restimulation of CTLs in PBLs with adenosine at IFNG base + 874, but not in PBLs homozygous for thymidine. Importantly, neutralization of TGF-β in hu PBL-SCID mice injected with A/A genotype PBLs resulted in reduced LPD development and expanded human CD8+ cells. Thus, our data show that TGF-β may promote tumor development by inhibiting CTL restimulation and expansion. Further, our data indicate that IFNG genotype may provide valuable information for both identifying transplant recipients at greater risk for PTLD and developing preventive and curative strategies.