2013年2月27日
Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway
Transplantation
- 巻
- 95
- 号
- 4
- 開始ページ
- 542
- 終了ページ
- 550
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1097/TP.0b013e31827b3d90
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. © 2013 by Lippincott Williams &
Wilkins.
Wilkins.
- リンク情報
-
- DOI
- https://doi.org/10.1097/TP.0b013e31827b3d90
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/23269193
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000315199200007&DestApp=WOS_CPL
- Scopus
- https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84874663240&origin=inward
- Scopus Citedby
- https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84874663240&origin=inward
- ID情報
-
- DOI : 10.1097/TP.0b013e31827b3d90
- ISSN : 0041-1337
- PubMed ID : 23269193
- SCOPUS ID : 84874663240
- Web of Science ID : WOS:000315199200007