2007 Fiscal Year Final Research Report Summary
Development of a novel therapeutic strategy for allergic disorders by targeting human hematopoietic progenitors
| Project/Area Number |
18604006
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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 |
アレルギー
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| Research Institution | Kyushu University |
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Principal Investigator |
IWASAKI Hiromi Kyushu University, Hospital, Assistant Professor (20403925)
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| Co-Investigator(Kenkyū-buntansha) |
AKASHI Koichi Kyushu University, Graduate School of Medical Sciences, Professor (80380385)
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| Project Period (FY) |
2006 – 2007
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| Keywords | eosinophil / basophil / mast cell / Progenitor / transcription factor / allergy / hypereosinophilic syndrome |
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| Research Abstract |
To establish effective therapeutic strategies for eosinophil-related disorders including allergic reactions and hypereosinophilic syndrome (HES) ,it should be important to understand the developmental pathway of human eosinophils by defining their lineage-committed progenitors. Here we isolate the human eosinophil lineage-committed progenitors (hEoPs) in the steady-state bone marrow according to the expression of Interleukin-5 receptor alpha chain (IL-5Rα) .IL-5Rα^+CD34^+CD38^+ hEoPs constituted 〜10% of the human common myeloid progenitor (hCMP) population, and gave rise exclusively to pure eosinophil colonies at 〜20% plating efficiency. Although blood basophils expressed IL-5Rα at a high level, progeny of IL-5Rα^+CD34^+CD38^+ cells never included histidine decarboxylase-expressing basophils. hEoPs developed in the culture of IL-5Rα- hCMPs, while neither megakaryocyte/erythrocyte progenitors nor granulocyte/macrophage progenitors, both of which develop downstream of hCMPs, generated CC
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chemokine receptor 3-expressing eosinophils in vitro. These observations indicate that the human eosinophil lineage diverges at the hCMP stage as a distinct pathway from the megakaryocyte/erythrocyte and the neutrophil/macrophage lineages. At this branchpoint, hEoPs upregulated GATA-1 and GATA-2 but not Friend of GATA-1. To clarify the physiological contribution of hEoPs to eosinophilopoiesis, we analyzed bone marrow samples from eosinophilia patients. The proportion of hEoPs in CD34^+ bone marrow progenitors 3-fold increased in eosinophilia patients including HES as compared with that in normal bone marrows (7.44 % vs. 2.38 %, p<0.01) .These data suggest that the hEoP stage is necessary for eosinophil differentiation and expansion, and that hEoPs might be a powerful tool to study pathogenesis of eosinophilia, and even be a critical therapeutic target in eosinophil-related disorders. To find the molecules that play critical roles in the hEoP development, we are planning to analyze the gene expression profile of hEoPs by the DNA microarray methodology. We are also trying to identify the human basophil/mast cell progenitor. Less
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