| Project/Area Number |
15K08402
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Experimental pathology
|
|---|
| Research Institution | Okayama University of Science (2018-2019)
Osaka University (2015-2017) |
|---|
Principal Investigator |
Mizuno Shinya 岡山理科大学, 理学部, 教授 (10219644)
|
|---|
| Project Period (FY) |
2015-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
|---|
| Keywords | HGF / c-Met / macrophages / immune response / cytokine storm / マクロファージ / 炎症性サイトカイン / 樹状細胞 / 断片化分子 / IDO / 免疫寛容 / オキシゲナーゼ / DC細胞 / IL-10 / HO-1 / 骨髄移植 / GVHD |
|---|
| Outline of Final Research Achievements |
Graft versus host disease is one of the most pathological events after bone marrow transplantation (BMT), with a clinical frequency of 30-50% among them. HGF is known to induce immunological tolerance in animal models of cardiac and renal transplantation, but it is still unclear how HGF acquires the tolerant responses at molecular levels. Thus, we used murine models of LPS- and BMT-induced inflammation to address the molecular basis of HGF-induced anti-immunological outcomes.
As a result, we found that blood HGF levels apparently increased in the murine models during systemic inflammation, associated with the increase in c-Met active levels in macrophages and possibly in DC cells. Importantly, HGF injection further enhanced the c-Met activation in these immunogenic cells, along with the decreased blood levels of inflammatory cytokines. In addition, we found that induction of IDO1 by HGF is, at least in part, responsible for the inhibitory effect of HGF on cytokine storm in vitro.
|
| Academic Significance and Societal Importance of the Research Achievements |
BM後に発症するGVHDはサイトカインストーム（CS）に依存する。CSは活性化したMφやDC細胞が放出する炎症性サイトカインの過剰な反応によってもたらされる。一方、HO1やIDO1といったオキシゲナーゼは炎症病態や自己免疫疾患において免疫寛容をもたらす。今回の研究によりこのような病態ではHGFがMφ/DC細胞などの免疫指令細胞を直接標的とし、オキシゲナーゼの誘導を介してCS抑制と免疫寛容を促す可能性を見いだした。CSはGVHDのみならず敗血症や新型コロナウイルス感染症などでも問題視される共通病態であり、HGF補充療法がこのような疾患を制圧する可能性を示した上で大きなインパクトを持つ。
|
