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IFN-γ-Stimulated Apoptotic Keratinocytes Promote Sclerodermatous Changes in Chronic Graft-Versus-Host Disease.

Authors
  • Saito, Akimasa1
  • Ichimura, Yuki1
  • Kubota, Noriko1
  • Tanaka, Ryota1
  • Nakamura, Yoshiyuki1
  • Fujisawa, Yasuhiro1
  • Watanabe, Rei1
  • Ishitsuka, Yosuke1
  • Fujimoto, Manabu2
  • Okiyama, Naoko3
  • 1 Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. , (Japan)
  • 2 Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan. , (Japan)
  • 3 Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: [email protected] , (Japan)
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Jun 01, 2021
Volume
141
Issue
6
Identifiers
DOI: 10.1016/j.jid.2020.09.033
PMID: 33242500
Source
Medline
Language
English
License
Unknown

Abstract

Patients with graft-versus-host disease (GVHD) develop characteristic mucocutaneous phenomena consisting of erosive erythema with histopathological findings including interface dermatitis and keratinocyte (KC) death, resulting in widespread sclerodermatous changes. We found that KCs exhibit marked production of TGFβ1 in skin lesions of chronic GVHD but not in those of acute GVHD. To further investigate the roles of KCs, the main targets of donor T cells, in sclerodermatous changes followed by interface dermatitis, we established a murine model of chronic GVHD-like sclerodermatous changes followed by acute GVHD-like mucocutaneous injury in genetically modified mice transferred with KC-specific CD8 T cells. Although transfer of granzyme B-deficient CD8 T cells did not result in either mucocutaneous injury or sclerodermatous changes in recipients, IFN-γ-deficient CD8 T-cell recipients developed severe acute mucocutaneous injury but milder sclerodermatous changes than wild-type CD8 T-cell recipients. Moreover, IFN-γ-deficient CD8 T-cell recipients had a lower expression of TGFβ1 in the epidermis than the control. Murine primary KCs undergoing FasL-induced apoptosis and incubated with IFN-γ produced TGFβ1, the production of which was inhibited by a pan-caspase inhibitor. Our results indicate that IFN-γ promotes TGFβ1 production by apoptotic KCs, which mediates the development of widespread sclerodermatous changes in KC-targeting GVHD. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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