Anti-inflammatory sFRP5 inhibits early B-lymphopoiesis in vivo

• Project/Area Number: 25461450
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: Fukushima Kentaro 大阪大学, 医学(系)研究科(研究院), 招聘教員 (70546879)
• Co-Investigator(Kenkyū-buntansha): YOKOTA Takafumi 大阪大学, 大学院医学系研究科, 助教 (60403200) ; ORITANI Kenji 大阪大学, 大学院医学系研究科, 准教授 (70324762) ; KANAKURA Yuzuru 大阪大学, 大学院医学系研究科, 教授 (20177489)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 免疫寛容 / リンパ球造血 / 造血幹細胞 / リンパ球分化 / リンパ球の分化・増殖

Outline of Final Research Achievements

Mammals have evolved to protect their offspring during early fetal development. Although fetuses represent mismatched allografts because of paternal genes, they develop with remarkable speed by obtaining optimal nutrition through the placenta. Thus, elaborate mechanisms induce tolerance of maternal immune system. We found that estrogen-induced Frizzled-related proteins (sFRPs), particularly sFRP5, suppress B-lymphopoiesis in vivo. Mice overexpressing sFRP5 had fewer B-lymphocytes in the peripheral blood and spleen. High levels of sFRP5 inhibited early B-cell differentiation in the bone marrow (BM), resulting in the accumulation of cells with a common lymphoid progenitor (CLP) phenotype. Conversely, sFRP5 deficiency reduced the number of hematopoietic stem cells and primitive lymphoid progenitors in the BM, particularly when estrogen was administered. Furthermore, a significant reduction in CLPs and B-lineage-committed progenitors was observed in the BM of sfrp5-null pregnant females.

Research Products

• [Journal Article] Quantitative polymerase chain reaction analysis with allele-specific oligonucleotide primers for individual IgH VDJ regions to evaluate tumor burden in myeloma patients. (2015)
  • Author(s): Sata H, Shibayama H, Maeda I, Habuchi Y, Nakatani E, Fukushima K, Fujita J, Ezoe S, Tadokoro S, Maeda T, Mizuki M, Kosugi S, Nakagawa M, Ueda S, Iida M, Tokumine Y, Azenishi Y, Mitsui H, Oritani K, Kanakura Y.
  • Journal Title: Exp Hematol. Volume: 印刷中 Issue: 5 Pages: 374-381
  • DOI: 10.1016/j.exphem.2015.01.002
  • Peer Reviewed
• [Journal Article] Estrogen-inducible sFRP5 inhibits early B-lymphopoiesis in vivo, but not during pregnancy (2015)
  • Author(s): Takafumi Yokota, Kenji Oritani, Takao Sudo, Tomohiko Ishibashi1, Yukiko Doi, Yoko Habuchi, Michiko Ichii, Kentaro Fukushima, Daisuke Okuzaki, Kazuma Tomizuka, Kengo Yamawaki, Makoto Kakitani, Akihiko Shimono, Eiichi Morii, Paul W. Kincade, Yuzuru Kanakura
  • Journal Title: European Journal of Immunology Volume: in press Issue: 5 Pages: 1390-1401
  • DOI: 10.1002/eji.201444939
  • Peer Reviewed / Open Access
• [Journal Article] Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine (2013)
  • Author(s): Maeda T, Hosen N, Fukushima K, Tsuboi A, Morimoto S, Matsui T, Sata H, Fujita J, Hasegawa K, Nishida S, Nakata J, Nakae Y, Takashima S, Nakajima H, Fujiki F, Tatsumi N, Kondo T, Hino M, Oji Y, Oka Y, Kanakura Y, Kumanogoh A, Sugiyama H
  • Journal Title: Blood Cancer J Volume: 3 Issue: 8 Pages: e130-e130
  • DOI: 10.1038/bcj.2013.29
  • Peer Reviewed
• [Journal Article] Complementary regulation of early B-lymphoid differentiation by genetic and epigenetic mechanisms. (2013)
  • Author(s): Yokota T, Sudo T, Ishibashi T, Doi Y, Ichii M, Orirani K, Kanakura Y.
  • Journal Title: Int J Hematol. Volume: 98 Issue: 4 Pages: 382-389
  • DOI: 10.1007/s12185-013-1424-7
  • Peer Reviewed
• [Presentation] SFRP5 inhibits early stages of B-cell differentiation and modulates estrogen-related changes in the immune system
  • Author(s): Takafumi Yokota, Kenji Oritani, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Yoko Habuchi, Michiko Ichii, Daisuke Okuzaki, Kazuma Tomizuka, Kengo Yamawaki, Makoto Kakitani, Akihiko Shimono, Eiichi Morii, Paul W. Kincade, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 55th Annual Meeting
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans, Louisiana, USA
• [Presentation] SFRP5 inhibits early B-lymphopoiesis and modulates estrogen-induced changes in the immune system.
  • Author(s): Takafumi Yokota, Kenji Oritani, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Michiko Ichii, Kazuma Tomizuka, Kengo Yamawaki, Akihiko Shimono, Yuzuru Kanakura
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌, 札幌市、北海道