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ID 52841
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Author
Sugiyama, Haruko
Yamasuji, Yoshiko
Shinagawa, Katsuji
Takeuchi, Kengo
Teshima, Takanori
Abstract
Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into OH model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with GSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT.
Keywords
Chronic graft-versus-host disease (GVHD)
Cyclosporine
Mammalian target of rapamycin (mTOR) inhibitor
Regulatory T cell
Published Date
2014-02
Publication Title
Biology of Blood and Marrow Transplantation
Volume
volume20
Issue
issue2
Start Page
183
End Page
191
ISSN
1083-8791
Content Type
Journal Article
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/52822
language
英語
Copyright Holders
(C) 2014 American Society for Blood and Marrow Transplantation.
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Refereed
True
DOI
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