title: Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors.
abstract: Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor-specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T-cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN-g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation.
authors.affiliation: Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA; The Departments of Surgery, Tokushima University, Tokushima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Morihito
authors.initials: M
authors.lastname: Takita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Chujo
authors.forename: Jeff A
authors.initials: JA
authors.lastname: SoRelle
authors.forename: Bashoo
authors.initials: B
authors.lastname: Naziruddin
authors.forename: Marlon F
authors.initials: MF
authors.lastname: Levy
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsumoto
mesh_terms: D064591:Allografts; D000818:Animals; D001803:Blood Transfusion; D002454:Cell Differentiation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D051858:Forkhead Transcription Factors / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A
keywords: T helper 17 cell; donor-specific transfusion; histone deacetylase inhibitor; islet transplantation; regulatory T cell