Novel mouse xenograft models reveal a critical role of CD4+ T cells in the proliferation of EBV-infected T and NK cells.
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.
Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo, Japan. imadome@nch.go.jp
Ken-ichi
K
Imadome
Misako
M
Yajima
Ayako
A
Arai
Atsuko
A
Nakazawa
Fuyuko
F
Kawano
Sayumi
S
Ichikawa
Norio
N
Shimizu
Naoki
N
Yamamoto
Tomohiro
T
Morio
Shouichi
S
Ohga
Hiroyuki
H
Nakamura
Mamoru
M
Ito
Osamu
O
Miura
Jun
J
Komano
Shigeyoshi
S
Fujiwara
D000293:Adolescent; D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002908:Chronic Disease; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis / Q000276:immunology / Q000821:virology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous