Interferon gamma stimulated apoptotic keratinocytes promote sclerodermatous changes in chronic graft versus host disease

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21253
• Project/Area Number (Other): 18H06138 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0803:Pathology, infection/immunology, and related fields
• Research Institution: University of Tsukuba
• Principal Investigator: Saito Akimasa 筑波大学, 附属病院, 病院講師 (70830181)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: 慢性移植片対宿主病 / TGFβ / 皮膚硬化 / 皮膚線維化 / IFNγ

Outline of Final Research Achievements

We established a new murine model of chronic GVHD-like scleroderma followed by acute GVHD-like mucocutaneous injury in genetically modified mice transferred with keratinocyte-specific CD8 T cells. While transfer of granzyme B-deficient CD8 T cells did not result in mucocutaneous injury followed by scleroderma in recipients, interferon (IFN)-γ-deficient CD8 T cell-recipient mice developed severe acute mucocutaneous injury, but milder scleroderma compared to wild-type CD8 T cell-recipients. Moreover, IFNγ-deficient CD8 T cell-recipient mice had lower expression of TGFβ1 in the epidermis than the control. Murine primary keratinocytes undergoing FasL-induced apoptosis and incubated with IFNγ produce TGFβ1, the production of which can be inhibited by a pan-caspase inhibitor. Collectively, our results indicate that IFNγ promotes TGFβ1 production by apoptotic keratinocytes, which mediates the development of scleroderma in keratinocyte-targeting GVHD.

Free Research Field

皮膚免疫

Academic Significance and Societal Importance of the Research Achievements

本研究により、慢性移植片対宿主病における皮膚硬化の新たなメカニズムを解明することができ、それにより、新しい治療起点、治療ターゲットを確立することできた。
それらに対しての新規治療薬の開発につながると考える。