Establishment of mouse model of chronic mucocutaneous candidiasis disease and use them to find therapeutic target

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670477
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: OKADA Satoshi 広島大学, 大学病院, 病院助教 (80457241)
• Co-Investigator(Kenkyū-buntansha): TSUMURA Miyuki 広島大学, 医師薬保健学研究院, 研究員 (80646274)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu 公益財団法人かずさDNA研究所, ヒトゲノム研究部, 研究室長 (20370926)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: STAT1 / CMCD / IL-17 / マウス

Outline of Final Research Achievements

We clarified the impact of STAT1 GOF mutations on the development of IL-17 producing T cells. We first investigated the effect of IFN-a/b, IFN-g and IL-27, cytokines that predominantly activate STAT1, in the differentiation of naive T cells into IL-17A-producing cells. We observed a much stronger reduction of the proportion of IL-17A T cells in the patients than in healthy controls. These data suggested that the poor development of IL-17 T cells in patients heterozygous for STAT1 alleles could result from enhanced IFNs and IL-27 responses via STAT1. We then treated cells with neutralizing antibodies (Abs) against IFN-a/b, IFN-g and IL-27. The combination of these Abs rescued the development of IL-17 T cells in CMCD patients carrying STAT1 mutations. These experiments established a key mechanism underlying impaired development of IL-17 T cells in the patients. This discovery also give us a new potential therapeutic target to cure host susceptibility to Candida in those patients.

Free Research Field

感染免疫