Abstract
Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.
Highlights
Epstein-Barr virus (EBV) is a ubiquitous c-herpesvirus that infects more than 90% of the adult population in the world
An exception was the CD4+ T-cell fraction isolated from patients with the CD4 type chronic active EBV infection (CAEBV), that reproducibly engrafted when transplanted without other components of PBMC (Figure 1A, Table 2)
The EBV DNA load observed in individual lymphocyte subsets in the patient 3 and a mouse that received her PBMC is shown as supporting data (Table S1)
Summary
Epstein-Barr virus (EBV) is a ubiquitous c-herpesvirus that infects more than 90% of the adult population in the world. EBV is occasionally involved in the pathogenesis of malignant tumors, such as Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma, along with the post-transplantation lymphoproliferative disorders in immunocompromised hosts. EBV has been consistently demonstrated in T or NK cells proliferating monoclonally or oligoclonally in a group of diseases including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) [5,6,7,8,9,10]. CAEBV, largely overlapping the systemic EBV+ T-cell lymphoproliferative diseases of childhood defined in the WHO classification of lymphomas [11], is characterized by prolonged or relapsing IM-like symptoms, unusual patterns of antibody responses to EBV, and elevated EBV DNA load in the peripheral blood [12,13,14]. CAEBV has a chronic time course with generally poor prognosis; without a proper treatment by hematopoietic stem cell transplantation, the Author Summary
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