The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder

Abstract

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication in organ transplant recipients and is most often associated with the Epstein Barr virus (EBV). EBV is a common gammaherpes virus with tropism for B lymphocytes and infection in immunocompetent individuals is typically asymptomatic and benign. However, infection in immunocompromised or immunosuppressed individuals can result in malignant B cell lymphoproliferations, such as PTLD. EBV+ PTLD can arise after primary EBV infection, or because of reactivation of a prior infection, and represents a leading malignancy in the transplant population. The incidence of EBV+ PTLD is variable depending on the organ transplanted and whether the recipient has preexisting immunity to EBV but can be as high as 20%. It is generally accepted that impaired immune function due to immunosuppression is a primary cause of EBV+ PTLD. In this overview, we review the EBV life cycle and discuss our current understanding of the immune response to EBV in healthy, immunocompetent individuals, in transplant recipients, and in PTLD patients. We review the strategies that EBV uses to subvert and evade host immunity and discuss the implications for the development of EBV+ PTLD.

Figure 1. Host defense systems in transplant recipients during EBV infection and PTLD

EBV transmission can occur A) in the community by entry through the oropharynx and/or B) via transplantation of a graft from an EBV+ donor. EBV establishes a productive lytic infection in which viral particles are produced and this process is targeted by NK cells (light orange) as well as CD4+ and CD8+ T cells (light gray and light green, respectively) specific for lytic cycle proteins. EBV transitions to latency III and B cells harbor the virus as an episome (red circle) and acquire a lymphoblastoid like phenotype like the EBV+ B cell lymphomas in PTLD. However, the expansion of these B cells can be controlled by CD4+ and CD8+ T cells (dark gray and dark green, respectively) specific for latent cycle proteins as well as by NK cells (dark orange). Through processes that are not completely understand the infected B cells can then transition to a latency 0/1 state in memory B cells (light yellow). Intermittently viral reactivation may occur and in some cases this may lead to the development of PTLD (red arrow) or control of latency III lymphoblastoid cells may be lost leading to PTLD (red arrow). EBV+ B cell lymphomas produce IL-10 (orange circles) that may further modulate function of EBV-specific T cells.