Development of a new therapeutic method for radiation-induced gastrointestinal syndrome targeting the innate immune system

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04257
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Radiation science
• Research Institution: Osaka City University (2018-2019); Chiba University (2017)
• Principal Investigator: Uematsu Satoshi 大阪市立大学, 大学院医学研究科, 教授 (50379088)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 放射線誘導性腸線維症 / 好酸球 / 抗体療法

Outline of Final Research Achievements

Radiation-induced intestinal fibrosis (RIF) is a serious complication after abdominal radiotherapy. Abdominal irradiation induced fibrosis of the submucosa associated with the excessive accumulation of eosinophils. Eosinophil-deficiency markedly ameliorated submucosal fibrosis post-irradiation. Irradiation elevated extracellular adenosine triphosphate levels, which in turned induced CCL11 and GM-CSF expression by submucosal pericryptal α-SMA+ cells that attracted and activated eosinophils, respectively. TGF-β from GM-CSF-stimulated eosinophils promoted collagen expression by α-SMA+ cells. Treatment with a newly developed IL-5 receptor alpha-targeting antibody, analogous to the human agent benralizumab, depleted intestinal eosinophils and suppressed radiation-induced submucosal fibrosis effectively. Collectively, we identified eosinophils as a crucial factor in the pathogenesis of RIF and showed a new therapeutic strategy for RIF targeting on eosinophils.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

消化管は放射線に対する感受性が非常に高く、癌の放射線治療において高線量の放射線に被曝すると、急性期から晩期に渡って多彩な障害が引き起こされ、効果的な予防・治療法の確立が強く求められている。特に、晩期の腸管の線維化は患者のQOLを著しく低下させるが、治療法がなかった。今回、好酸球による病態形成を明らかにし、好酸球除去抗体が有効な治療法となることをマウスで示したことは非常に大きな成果である。この抗体の人アナログは既に重症気管支喘息で、実用化されている。今後、RIFの新しい治療法が確立するのもそう遠くないと考える。学術的だけでなく、社会的にも重要な成果を得ることができた。