title: Induction of donor-specific tolerance by adenovirus-mediated CD40Ig gene therapy in rat liver transplantation.
abstract: BACKGROUND
  Blockade of CD40-CD40 ligand (CD154) costimulatory pathway with anti-CD154 antibody (Ab) prolongs allograft survival in experimental organ transplantations; however, repeated agent administration is needed to provide an adequate immunosuppression. Seeking for simple and effective approach to interfere this signaling, we applied adenovirus-mediated gene therapy by encoding CD40Ig gene (AdCD40Ig).
  
  
  METHODS
  Liver graft from ACI (RT1av1) rat was transplanted orthotopically into LEW (RT1l) rat, and AdCD40Ig was given to animals via the penile vein immediately after grafting (n=6).
  
  
  RESULTS
  A single treatment with AdCD40Ig at 1x10(9) plaque forming units induced specific expression of CD40Ig gene on allograft liver, produced substantial amount of the protein in the sera, and allowed indefinite graft survival. Whereas, LEW recipients given no treatment or control adenovirus vector (AdLacZ) promptly rejected ACI liver. In addition, AdCD40Ig-treated, long-term survivors accepted skin graft from the donor strain but not the third party graft. Histopathology revealed that liver structure of the long-term surviving animals was completely preserved in normal with no infiltration of mononuclear cells.
  
  
  CONCLUSIONS
  Blockade of CD40-CD154 pathway by CD40Ig gene therapy is a potent alloantigen-specific immunosuppressive strategy to induce permanent acceptance of liver allograft and would be a new therapeutic candidate in a clinical liver transplantation.
authors.affiliation: First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Nomura
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
authors.forename: Megumi
authors.initials: M
authors.lastname: Takehara
authors.forename: Hayato
authors.initials: H
authors.lastname: Echizenya
authors.forename: Masao
authors.initials: M
authors.lastname: Sunahara
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kitagawa
authors.forename: Miri
authors.initials: M
authors.lastname: Fujita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.forename: Toshimistu
authors.initials: T
authors.lastname: Uede
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019013:CD40 Antigens / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006085:Graft Survival; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D019076:Transgenes / Q000235:genetics; D023001:Transplantation Tolerance
chemical_list: D019013:CD40 Antigens; D007074:Immunoglobulin G