| Project/Area Number |
13307012
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | THE UNIVERSITY OF TOKYO |
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Principal Investigator |
TAKATSU Kiyoshi The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (10107055)
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| Co-Investigator(Kenkyū-buntansha) |
HORIKAWA Keisuke The University of Tokyo, The Institute of Medical Science, Research Assistant (Associate), 医科学研究所, 助手 (60313095)
NISITANI Sazuku The University of Tokyo, The Institute of Medical Science, Research Assistant (Associate), 医科学研究所, 助手 (10322075)
TAKAKI Satoshi The University of Tokyo, The Institute of Medical Science, Associate Professor, 医科学研究所, 助教授 (10242116)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥55,250,000 (Direct Cost: ¥42,500,000、Indirect Cost: ¥12,750,000)
Fiscal Year 2003: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2002: ¥22,230,000 (Direct Cost: ¥17,100,000、Indirect Cost: ¥5,130,000)
Fiscal Year 2001: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000)
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| Keywords | IL-5 / B CELLS / CD38 / CLASS SWITCH RECOMBINATION / BTK / AID / BLIMP-1 / APS / アダプター分子 / クラススイッチ / B-1細胞 / ホメオスターシス / B細胞分化 / 粘膜免疫 / IgHクラススイッチ組み換え / NF-KB / STAT5 / IgA / BAM11 |
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| Research Abstract |
Interleukin 5 (IL-5) induces proliferation and differentiation of B cells by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, α and β(βc). In this project, we attempted to elucidate the role of IL-5 in B-cell proliferation and differentiation. We found that the IL-5/IL-5R system plays an important role in maintaining the number and the cell size as well as the functions of mature B-1 cells. The administration of anti-IL-5 mAb into wild-type (WT) mice, T -cell-depleted mice or mast cell-depleted mice resulted in reduction in the total number and cell size of B-1 cells to a similar extent to IL-5Rα-deficient (IL-5Rα^<-/->) mice. Cell transfer experiments have demonstrated that B-1 cell survival in WT mice and homeostatic proliferation in RAG-2^<-/-> mice are impaired in the absence of the IL-5Rα. IL-5 stimulation of WT B-1 cells, but not IL-5Rα ^<-/-> B-1 cells, enhances CD40 expression and augments IgM and IgG production following stimulation with
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anti-CD40 mAb. Enhanced IgA production in feces induced by the oral administration of LPS was not observed in IL-5Rα^<-/-> mice. Our results illuminate the role of IL-5 in the homeostatic proliferation and survival of mature B-1 cells and in IgA production in the mucosal tissues.
IL-5 stimulation of CD38-activated murine splenic B cells induces μ-γ1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent m-g1 CSR. We examined the activation of Stat by IL-5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells. The role of Stat5a and Stat5b in IL-5-induced μ-γ1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a^<-/-> / and Stat5b^<-/-> mice. Expression levels of CD38-induced germline γ1 transcripts and of AID in Stat5a^<-/-> /-and Stat5b^<-/->/ B cells upon IL-5 stimulation were comparable to those of WT B cells. The impaired μ-γ1 CSR by Stat5b^<-/-> B cells, but not by Stat5a^<-/-> / B cells, was rescued in part by IL-4. Analysis of cell division cycle number of WT B cells revealed that μ-γ1 CSR was observed after five to six cell divisions. Stat5a^<-/-> / and Stat5b^<-/->/ B cells showed similar cell division cycles, but they did not undergo μ-γ1 CSR. Our data supports the notion that both Stat5a and Stat5b are essential for IL-S-dependent μ-γ1 CSR and Ig secretion, however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function. Less
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