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

作者：Imadome Ken Ichi^*; Yajima Misako; Arai Ayako; Nakazawa Atsuko; Kawano Fuyuko; Ichikawa Sayumi; Shimizu Norio; Yamamoto Naoki; Morio Tomohiro; Ohga Shouichi; Nakamura Hiroyuki; Ito Mamoru; Miura Osamu; Komano Jun; Fujiwara Shigeyoshi

来源：PLoS Pathogens, 2011, 7(10): e1002326.

DOI：10.1371/journal.ppat.1002326

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-2R gamma(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-gamma, 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.

• 出版日期2011-10