start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=2 article-no= start-page=183 end-page=191 dt-received= dt-revised= dt-accepted= dt-pub-year=2014 dt-pub=201402 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease en-subtitle= kn-subtitle= en-abstract= kn-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. en-copyright= kn-copyright= en-aut-name=SugiyamaHaruko en-aut-sei=Sugiyama en-aut-mei=Haruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NishimoriHisakazu en-aut-sei=Nishimori en-aut-mei=Hisakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamasujiYoshiko en-aut-sei=Yamasuji en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsuokaKen-ichi en-aut-sei=Matsuoka en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KondoEisei en-aut-sei=Kondo en-aut-mei=Eisei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShinagawaKatsuji en-aut-sei=Shinagawa en-aut-mei=Katsuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TakeuchiKengo en-aut-sei=Takeuchi en-aut-mei=Kengo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TeshimaTakanori en-aut-sei=Teshima en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TanimotoMitsune en-aut-sei=Tanimoto en-aut-mei=Mitsune kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=2 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=3 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=4 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=5 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=6 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=7 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=8 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol affil-num=9 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pathol affil-num=10 en-affil= kn-affil=Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Target affil-num=11 en-affil= kn-affil=Hokkaido Univ, Dept Hematol affil-num=12 en-affil= kn-affil=Okayama Univ, Gradu Sch Med Dent & Pharmaceut Sci, Dept Hematol & Oncol en-keyword=Chronic graft-versus-host disease (GVHD) kn-keyword=Chronic graft-versus-host disease (GVHD) en-keyword=Cyclosporine kn-keyword=Cyclosporine en-keyword=Mammalian target of rapamycin (mTOR) inhibitor kn-keyword=Mammalian target of rapamycin (mTOR) inhibitor en-keyword=Regulatory T cell kn-keyword=Regulatory T cell END