Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent alloimmune responses and permits long-term islet allograft acceptance

Masaaki Watanabe, Kenichiro Yamashita, Hirofumi Kamachi, Daisuke Kuraya, Yasuyuki Koshizuka, Susumu Shibasaki, Yoh Asahi, Hitoshi Ono, Shin Emoto, Masaomi Ogura, Tadashi Yoshida, Michitaka Ozaki, Kazuo Umezawa, Michiaki Matsushita, Satoru Todo

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Abstract

BACKGROUND: Long-term graft deterioration remains a major obstacle in the success of pancreatic islet transplantation (PITx). Antigen-independent inflammatory and innate immune responses strengthen subsequent antigen-dependent immunity; further, activation of nuclear factor (NF)-κB plays a key role during these responses. In this study, we tested our hypothesis that, by the inhibition of NF-κB activation, the suppression of these early responses after PITx could facilitate graft acceptance. METHODS: Full major histocompatibility complex (MHC)-mismatched BALB/c (H-2) mice islets were transplanted into streptozotocin-induced diabetic C57BL/6 (B6: H-2) mice. The NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) was administered for either 3 or 14 days after PITx. To some PITx recipients, tacrolimus was also administered. Islet allograft survival, alloimmune responses, and in vitro effects of DHMEQ on dendritic cells (DCs) were assessed. RESULTS: With a vehicle treatment, 600 islet allografts were promptly rejected after PITx. In contrast, 3-day treatment with DHMEQ, followed by 2-week treatment with tacrolimus, allowed permanent acceptance of islet allografts. The endogenous danger-signaling molecule high mobility group complex 1 (HMGB1) was elevated in sera shortly after PITx, whereas DHMEQ administration abolished this elevation. DHMEQ suppressed HMGB1-driven cellular activation and proinflammatory cytokine secretion in mouse bone marrow-derived DCs and significantly reduced the capacity of DCs to prime allogeneic T-cell proliferation in vitro. Finally, the DHMEQ plus tacrolimus regimen reverted the diabetic state with only 300 islet allografts. CONCLUSIONS: Inhibition of NF-κB activation by DHMEQ shortly after PITx suppresses HMGB1, which activates DCs and strengthens the magnitude of alloimmune responses; this permits long-term islet allograft acceptance, even in case of fewer islet allografts.

Original languageEnglish
Pages (from-to)454-462
Number of pages9
JournalTransplantation
Volume96
Issue number5
DOIs
Publication statusPublished - 18-07-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Transplantation

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    Watanabe, M., Yamashita, K., Kamachi, H., Kuraya, D., Koshizuka, Y., Shibasaki, S., Asahi, Y., Ono, H., Emoto, S., Ogura, M., Yoshida, T., Ozaki, M., Umezawa, K., Matsushita, M., & Todo, S. (2013). Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent alloimmune responses and permits long-term islet allograft acceptance. Transplantation, 96(5), 454-462. https://doi.org/10.1097/TP.0b013e31829b077f