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The role of Wilms' tumor gene peptide-specific cytotoxic T lymphocytes in immunologic selection of a paroxysmal nocturnal hemoglobinuria clone.

Ikeda K, Shichishima T, Yasukawa M, Nakamura-Shichishima A, Noji H, Akutsu K, Osumi K, Maruyama Y

First Department of Internal Medicine, Fukushima Medical University, 1 Hikariga-oka, Fukushima 960-1295, Japan.

OBJECTIVE: To clarify an expansion mechanism of a paroxysmal nocturnal hemoglobinuria (PNH) clone with the Wilms' tumor gene (WT1). MATERIALS AND METHODS: In PNH patients with the HLA-A*2402 allele, frequencies of peripheral blood (PB) WT1 peptide-specific and HLA-A*2402-restricted CD8+ cells and WT1 peptide-stimulated interferon-gamma-producing mononuclear cells (MNCs), cytotoxicity of WT1 peptide-specific and HLA-A*2402-restricted cytotoxic T lymphocyte (CTL) clone (TAK-1) cells on bone marrow (BM) MNCs, and after co-incubation with TAK-1 cells, changes in colony-forming unit granulocyte-macrophage colony formation of CD34+ cells and in CD59 expression in viable CD34+ cells were investigated. RESULTS: The frequencies of PB WT1 peptide-specific and HLA-A*2402-restricted CD8+ cells (p < 0.005) and WT1 peptide-stimulated interferon-gamma-producing MNCs (p < 0.02) were significantly higher in 5 PNH patients than 8 healthy volunteers (HV). In 5 PNH patients or 3 HV, TAK-1 cells significantly killed BMMNCs and suppressed colony formations of CD34+CD59+ and/or CD34+CD59- cells in the absence and presence of a WT1 peptide or only in the presence of the peptide, respectively, in an HLA-restricted manner. After co-incubation with TAK-1 cells, reduction rates of colony formation of CD34+CD59- cells were significantly less than those of CD34+CD59+ cells in 5 PNH patients (p < 0.002) and proportions of viable CD34+CD59- cells from 5 PNH patients significantly increased in the absence (p < 0.01) and presence (p < 0.01) of a WT1 peptide in an HLA-restricted manner. CONCLUSION: WT1 peptide-specific and HLA-restricted CTLs may play an important role in expansion of a PNH clone during immunologic selection and/or in the occurrence of BM failure via interferon-gamma in PNH.

Published 23 March 2007 in Exp Hematol, 35(4): 618-26.
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