title: 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.
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.
authors.affiliation: First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kamachi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kuraya
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Koshizuka
authors.forename: Susumu
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Yoh
authors.initials: Y
authors.lastname: Asahi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ono
authors.forename: Shin
authors.initials: S
authors.lastname: Emoto
authors.forename: Masaomi
authors.initials: M
authors.lastname: Ogura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Michiaki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D003512:Cyclohexanones / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D006085:Graft Survival; D024243:HMGB1 Protein / Q000097:blood; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011183:Postoperative Complications / Q000517:prevention & control*; D016559:Tacrolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D016207:Cytokines; D024243:HMGB1 Protein; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin; D016559:Tacrolimus