title: Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway.
abstract: BACKGROUND
  A newly developed compound, 3-[(dodecylthiocarbonyl)methyl]-glutarimide (DTCM-G), has been shown to inhibit nuclear translocation of c-Fos/c-Jun in a murine macrophage cell line. Herein, we studied the immunosuppressive properties and potency of DTCM-G.
  
  
  METHODS
  Using purified mouse T cells, the in vitro effects of DTCM-G on activation, cytokine production, proliferation, and cell cycle progression were assessed, and a possible molecular target of DTCM-G was investigated. In a BALB/c (H-2(d)) to C57BL/6 (H-2(d)) mouse heart transplantation model, transplant recipients were administered DTCM-G, a calcineurin inhibitor (tacrolimus), and a nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). Treatment drugs were administered daily for 14 days after transplantation. Alloimmune responses were assessed in addition to graft survival time.
  
  
  RESULTS
  After anti-CD3+anti-CD28 monoclonal antibody stimulation, DTCM-G significantly suppressed proliferation, interferon-γ production, and cell cycle progression of activated T cells but not CD25 expression or interleukin-2 production. These effects were accompanied by inhibition of 70-kDa S6 protein kinase phosphorylation, a downstream kinase of the mammalian target of rapamycin. The addition of tacrolimus and DHMEQ to DTCM-G resulted in a robust inhibition of T-cell proliferation. In vivo combination therapy of DTCM-G plus either tacrolimus or DHMEQ significantly suppressed alloreactive interferon-γ-producing precursors and markedly prolonged cardiac allograft survival. Furthermore, combination of all three agents markedly inhibited alloimmune responses and permitted long-term cardiac allograft survival.
  
  
  CONCLUSIONS
  DTCM-G inhibits T cells by suppressing the downstream signal of mammalian target of rapamycin. DTCM-G in combination with tacrolimus and DHMEQ induces a strong immunosuppressive effect in vivo.
authors.affiliation: Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Goto
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakayama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tsunetoshi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Zaitsu
authors.forename: Rumi
authors.initials: R
authors.lastname: Igarashi
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003512:Cyclohexanones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D010881:Piperidones / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: C573776:3-((dodecylthiocarbonyl)methyl)glutarimide; D001549:Benzamides; D065095:Calcineurin Inhibitors; D003512:Cyclohexanones; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D010881:Piperidones; C464444:dehydroxymethylepoxyquinomicin; D007371:Interferon-gamma; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D016559:Tacrolimus