Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway

Susumu Shibasaki, Kenichiro Yamashita, Ryoichi Goto, Kenji Wakayama, Yusuke Tsunetoshi, Masaaki Zaitsu, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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) to C57BL/6 (H-2) 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.

Original languageEnglish
Pages (from-to)542-550
Number of pages9
JournalTransplantation
Volume95
Issue number4
DOIs
Publication statusPublished - 27-02-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Transplantation

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