| Project/Area Number |
16590946
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kumamoto University |
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Principal Investigator |
KAWAGUCHI Tatsuya Kumamoto Univ., School of Medicine, Associate Professor, 医学部附属病院, 助教授 (50244116)
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| Co-Investigator(Kenkyū-buntansha) |
HORIKAWA Kentaro Kumamoto Univ., Graduate School of Medical and Pharmaceutical Sciences, Senior Staff, 大学院・医学薬学研究部, 助手 (40322309)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Paroxysmal nocturnal hemoglobinuria / Bone marrow failure / Natural killer cells / stress-inducible protein / GPI anchored proteins / ULBP / MICA / B / ストレス誘導蛋白 |
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| Research Abstract |
Paroxysmal nocturnal hemoglobinuria (PNH) and idiopathic aplastic anemia (AA) share immune-mediated bone marrow (BM) injury. However, the precise mechanism of the BM injury remains unknown. Recently, we showed that leukemic K562 cells were less sensitive to natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIG-A mutations (Nagakura et al., Blood 2002 ; 100 : 1031-37). In the present study, we found that the decreased NK sensitivity of the leukemic cells was conferred by a deficiency of stress-inducible GPI-linked membrane UL16 binding proteins (ULBP) that activate NK and T cells, indicating that ULBP appeared on blood cells can intensify NK cell-mediated cytotoxicity in vitro. Of clinical interest, we found some PNH patients harboring ULBP-expressing (ULBP^+) blood cells. Thus, we expected that ULBP^+ cells could be injured by autologous cytotoxic effector cells (NK and CD8^+ T cells) expressing NKG2D, a receptor for ULBP. Actually, granulocytes of PNH patients carrying ULBP^+ granulocytes were shown to be susceptible to killing by autologous peripheral blood mononuclear cells including the effector cells. In contrast, the ULBP-associated killing was not observed in healthy donors nor PNH patients who had no ULBP^+ granulocytes. These results suggest that PNH patients undergo ULBP-associated marrow injury if they sustain pathogenic pressure to induce the stress proteins. We therefore conclude that the ULBP-NKG2D engagement is implicated in the pathogenesis of BM failure in a proportion of patients with BM failure syndromes and that the membrane expression of ULBP could be a useful clinical marker of immune-mediated marrow injury.
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