title: Mammalian target of rapamycin inhibitors permit regulatory T cell reconstitution and inhibit experimental chronic graft-versus-host disease.
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 C3H 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 CSA, 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.
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Haruko
authors: H
authors: Sugiyama
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. Electronic address: yosmaeda@md.okayama-u.ac.jp.
authors: Yoshinobu
authors: Y
authors: Maeda
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Hisakazu
authors: H
authors: Nishimori
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Yoshiko
authors: Y
authors: Yamasuji
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Ken-ichi
authors: K
authors: Matsuoka
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Nobuharu
authors: N
authors: Fujii
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Eisei
authors: E
authors: Kondo
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Katsuji
authors: K
authors: Shinagawa
authors: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Takehiro
authors: T
authors: Tanaka
authors: Pathology Project for Molecular Target, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Kengo
authors: K
authors: Takeuchi
authors: Department of Hematology, Hokkaido University, Hokkaido, Japan.
authors: Takanori
authors: T
authors: Teshima
authors: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Mitsune
authors: M
authors: Tanimoto
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Chronic graft-versus-host disease (GVHD); Cyclosporine; Mammalian target of rapamycin (mTOR) inhibitor; Regulatory T cell