The Development Of An In Vivo Humanized Mouse Model To Investigate Epstein-Barr Virus Infection And Tumorigenesis

Abstract

Epstein-Barr virus (EBV) infection is associated with aggressive malignancies including post-transplant lymphoproliferative disease (PTLD). The high prevalence and the benign nature of latent EBV infection make its pathogenic role questionable. Although immunosuppression allows outgrowth of EBV-transformed B lymphocytes, its withdrawal fails to achieve a complete response, implying that other factors are involved in the development of EBV-related PTLD. To address this, we have developed a humanized mouse model of EBV infection. B lymphocyte depletion resulted in a significant survival benefit in infected mice, highlighting a pivotal role of infected B lymphocytes in disease pathogenesis. A secondary transfer lymphoproliferative disease model proved the tumorigenic potential of infected B lymphocytes and showed these cells are necessary and sufficient to form lymphoproliferative lesions in severely immunocompromised hosts. Our findings prove the causal relationship between EBV and PTLD and suggested that early incorporation of B lymphocyte depletion regimens may be beneficial.