Impaired cytotoxic T lymphocyte response to Epstein-Barr virus-infected NKcells in patients with severe chronic active EBV infection

Clinical evidence of a relationship between severe chronic active Epstein-B arr virus (EBV) infection and clonal expansion of EBV-infected T or NK cell s has been accumulated. In order to clarify pathogenesis of EBV-infected ce ll proliferation in patients with severe chronic active EBV infection, cyto toxic T lymphocyte (CTL) responses of two patients against B-lymphoblastoid cell lines (B-LCL) and EBV-infected NK cells were examined in comparison w ith those of HLA-identical healthy siblings. Unexpectedly, patients' CTL ac tivities induced by mixed culture with autologous B-LCLs were markedly redu ced, although uncontrolled EBV-related B-cell proliferations have never bee n experienced. In contrast, limiting dilution analysis demonstrated that B- LCL-specific CTL precursor (CTLp) frequencies of patients were comparable t o those of their healthy sisters. The existence of normal levels of B-LCL-s pecific T cell responses was confirmed by flow-cytometric analysis of IFN-g amma -producing T cells after stimulation with B-LCLs. Infected NK-cell-spe cific 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-cel l-specific CTL clones could be established. From these findings, two treatm ent options for severe chronic active EBV infection are offered for conside ration: adoptive transfer of in vitro-cultured CTL, and bone marrow transpl antation from HL4-identical donors. (C) 2001 Wiley-Liss. Inc.