Novel Mouse Xenograft Models Reveal a Critical Role of CD4+ T Cells in the Proliferation of EBV-Infected T and NK Cells

• DOI: 10.1371/journal.ppat.1002326
• Publication Date: 2011-10-20T21:04:32Z
• Authors: Ken-Ichi Imadome; Misako Yajima; Ayako Arai; Atsuko Nakazawa; Fuyuko Kawano; Sayumi Ichikawa; Norio Shimizu; Naoki Yamamoto; Tomohiro Morio; Shouichi Ohga; Hiroyuki Nakamura; Mamoru Ito; Osamu Miura; Jun Komano; Shigeyoshi Fujiwara
• Keywords: Adult; CD4-Positive T-Lymphocytes; Male; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Adolescent; QH301-705.5; Lymphohistiocytosis, Hemophagocytic; Mice; 03 medical and health sciences; Mice, Inbred NOD; Animals; Humans; Biology (General); Child; Cells, Cultured; Cell Proliferation; 0303 health sciences; Infant; RC581-607; 3. Good health; Killer Cells, Natural; Disease Models, Animal; Chronic Disease; Host-Pathogen Interactions; Female; Immunologic diseases. Allergy; Research Article

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-2Rγ(null) 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.