2002 Fiscal Year Final Research Report Summary
MECHANISM FOR SELECTIVE EXPANSION OF A PIG-A MUTANT IN PAROXYSMAL NOCTURNAL HEMOGLOBINEMIA
| Project/Area Number |
13671070
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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 UNIVERSITY SCHOOL OF MEDICINE, KOSHI (ASSISTANT PROFESSOR), 医学部附属病院, 講師 (50244116)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAKURA Shoich KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE, CLINICAL STUFF, 医学部附属病院, 医員
ISHIHARA Sonoko KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE, CLINICAL STUFF, 医学部附属病院, 医員
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| Project Period (FY) |
2001 – 2002
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| Keywords | Paroxysmal nocturnal hemoglobinuria / PIG-A gene / bone marrow failure / glycosylphosphatidylinositol (GPI)-anchored proteins / natural killer cells / clonal expansion |
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| Research Abstract |
Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease characterized by hemolysis, venous thrombosis and marrow failure. A mechanism of hemolysis has been only elucidated. PNH cells lack glycosylphosphatidylinositol-anchored proteins (GPI-AP) including compliment regulatory proteins such as DAF and CD59, leading to increased sensitivity of erythrocytes to the lytic action of complement. The deficiency is caused by a somatic mutation of the PIG-A gene. Our current major concern is the mechanism by which a PNH clone expands. Increasing evidence has been shown that the presence of the mutation alone does not induce the expansion. To explain this issue, two hypotheses are proposed: a growth or a survival advantage theory. The latter indicates that PNH cells escape immune attack in the setting of immune-mediated bone marrow injury often observed in PNH patients. The present study was aimed to prove this hypothesis by verifying the escape mechanism in vitro.
We first p
… More
repared GPI-AP-deficient cell lines and control counterparts fully recovered with the expression of GPI-AP by transfection of PIG-A cDNA, and examined the sensitivity of these cells to killing by natural killer (NK) cells using ^<51>Cr-release assay. To both primary and cultured NK cells, GPI-AP-deficient cells were less susceptible than their control counterparts. NK activity was completely abolished with concanamycin A and by calcium chelation, indicating that killing was preforin-dependent. There were no differences in major histocompatibility classes I expression or sensitivity to either purified perforin or to interleukin-2-activated NK cells between GPI-AP-deficient cells and control cells. From these results we infer that GPI-AP-deficient cells lack molecules needed for NK activation or to trigger perforin-medicated killing. Our experiments suggest that PIG-A mutations confer a relative survival advantage to a PNH clone, contributing to selective expansion of these cells in the setting of marrow injury by cytotoxic lymphocytes. (296 words) Less
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Research Products
(10 results)
