title: Immunomodulatory effect of nuclear factor-κB inhibition by dehydroxymethylepoxyquinomicin in combination with donor-specific blood transfusion.
abstract: BACKGROUND
  Nuclear factor-κB (NF-κB) is a key molecule in alloimmune responses, however, its role in tolerance induction is not clear. We have previously reported that dehydroxymethylepoxyquinomycin (DHMEQ), a novel NF-κB inhibitor, prolongs cardiac allograft survival. In this study, we evaluated the immunomodulatory effects of DHMEQ when combined with a donor-specific blood transfusion (DST), and assessed whether the treatment induces tolerance in a mouse heart transplantation model.
  
  
  METHODS
  DST (20×10 splenocytes) was given intravenously at day -7. DHMEQ (30 mg/kg/day) was administered intraperitoneally for 14 days after DST. Graft survival and histology were evaluated. The underlying mechanisms of immunomodulation by DST and DHMEQ treatments were investigated by assessing alloimmune responses after transplantation.
  
  
  RESULTS
  In fully mismatched H2-to-H2 heart transplants, DST alone prolonged allograft median survival time to 15 days, whereas when DST was combined with DHMEQ treatment, the graft median survival time was prolonged to 39.5 days. When the donor-recipient strain combination was reversed, that is, H2-to-H2, heart transplants were accepted (>150 days survival) in more than 60% of recipients treated with a DST and DHMEQ, whereas control allografts were all rejected within 8 days. The combined therapy markedly inhibited immune responses by both the direct and indirect allorecognition pathways mainly attributed to promotion of activation-induced cell death and Treg generation.
  
  
  CONCLUSIONS
  Our results demonstrate the distinctive ability of NF-κB inhibition in combination with donor alloantigen to promote transplantation tolerance through multiple cellular mechanisms.
authors.affiliation: First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Goto
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueki
authors.forename: Motohiro
authors.initials: M
authors.lastname: Uno
authors.forename: Tetsu
authors.initials: T
authors.lastname: Oura
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Rumi
authors.initials: R
authors.lastname: Igarashi
authors.forename: Susumu
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakayama
authors.forename: Gentaro
authors.initials: G
authors.lastname: Hirokata
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Zaitsu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001803:Blood Transfusion; D003131:Combined Modality Therapy; D003512:Cyclohexanones / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D006183:H-2 Antigens; D007155:Immunologic Factors; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin