Impaired cytotoxic T lymphocyte response to Epstein-Barr virus-infected NK cells in patients with severe chronic active EBV infection.
Clinical evidence of a relationship between severe chronic active Epstein-Barr virus (EBV) infection and clonal expansion of EBV-infected T or NK cells has been accumulated. In order to clarify pathogenesis of EBV-infected cell proliferation in patients with severe chronic active EBV infection, cytotoxic T lymphocyte (CTL) responses of two patients against B-lymphoblastoid cell lines (B-LCL) and EBV-infected NK cells were examined in comparison with those of HLA-identical healthy siblings. Unexpectedly, patients' CTL activities induced by mixed culture with autologous B-LCLs were markedly reduced, although uncontrolled EBV-related B-cell proliferations have never been experienced. In contrast, limiting dilution analysis demonstrated that B-LCL-specific CTL precursor (CTLp) frequencies of patients were comparable to those of their healthy sisters. The existence of normal levels of B-LCL-specific T cell responses was confirmed by flow-cytometric analysis of IFN-gamma-producing T cells after stimulation with B-LCLs. Infected NK-cell-specific CTLp frequencies of the patients were at undetectable levels despite their expression of latent membrane protein (LMP) 1, suggesting mechanisms to escape immunologic surveillance. In the patients' HLA-identical healthy sisters, infected NK-cell-specific CTLps were detected, and infected NK-cell-specific CTL clones could be established. From these findings, two treatment options for severe chronic active EBV infection are offered for consideration: adoptive transfer of in vitro-cultured CTL, and bone marrow transplantation from HLA-identical donors.
Tsuge
I
I
Department of Pediatrics, Nagoya University School of Medicine, Tsurumai-Cho 65, Showa-Ku, Nagoya 466-8550, Japan.
Morishima
T
T
Kimura
H
H
Kuzushima
K
K
Matsuoka
H
H
D000293:Adolescent; D000485:Allergens; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002908:Chronic Disease; D002999:Clone Cells; D018920:Coculture Techniques; D009033:Culicidae / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000485:Allergens; D007371:Interferon-gamma