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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1558-1565.
Prepublished online as a Blood First Edition Paper on October 21, 2004; DOI 10.1182/blood-2003-07-2476.
 Previous Article | Next Article 
Submitted July 22, 2003
Accepted September 25, 2004
IFN-gamma gene polymorphisms associate with development of EBV-positive Lymphoproliferative Disease in hu PBL SCID mice
Julie E Dierksheide, Robert A Baiocchi, Amy K Ferketich, Sameek Roychowdhury, Ronald P Pelletier, Charles F Eisenbeis, Michael A Caligiuri, and Anne M VanBuskirk*
Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH, USA
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State Univeristy, Columbus, OH, USA; Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Division of Epidemiology and Biometrics, The Ohio State University, Columbus, OH, USA
Department of Medical Microbiology, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
Division of Transplantation, Department of Surgery, The Ohio State University, Columbus, OH, USA
Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH, USA; Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
* Corresponding author; email: vanbuskirk.1{at}osu.edu.
Post-transplant lymphoproliferative disorder (PTLD) is a devastating post-transplant complication often associated with Epstein-Barr virus. While type and length of immunosuppression are risk factors, a patient's inherent immune capacity also likely contributes to this disorder. This report utilizes severe combined-immunodeficient mice injected with human peripheral blood leukocytes (hu PBL-SCID mice) to test the hypothesis that cytokine genotype associates with development of EBV-associated lymphoproliferative disease (LPD). We observed that the A/A genotype for base +874 of the IFN- gene was significantly more prevalent in PBL producing rapid, high penetrance LPD in hu PBL-SCID mice, compared to PBL producing late, low penetrance LPD or no LPD. In examining the relationship between genotype and cytolytic T-lymphocyte (CTL) function, TGF- inhibited re-stimulation of CTL in PBL with adenosine at IFN- base +874, but not in PBL homozygous for thymidine. Importantly, neutralization of TGF- in hu PBL-SCID mice injected with A/A genotype PBL resulted in reduced LPD development and expanded human CD8+ cells. Thus, our data show that TGF- may promote tumor development by inhibiting CTL restimulation and expansion. Further, our data indicate that IFN- genotype may provide valuable information for both identifying transplant recipients at greater risk for PTLD, and developing preventative and curative strategies.
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