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

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-restrieted 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 coincubation 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. WTI 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. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.