title: Development of donor-specific immunoregulatory T-cells after local CTLA4Ig gene transfer to pancreatic allograft.
abstract: BACKGROUND
  CTLA4Ig gene transfer directly to graft tissue might have the potential to avoid the need for systemic immunosuppression. In our previous studies of bio-breeding (BB) rats, local adenovirus-mediated CTLA4Ig gene transfer protected the pancreas from autoimmune and alloimmune responses. This study investigated the potency of local CD28/B7 costimulatory blockade for induction of donor-specific tolerance and further examined the existing mechanisms.
  
  
  METHODS
  Brown Norway (BN; RT1)-pancreaticoduodenal grafts transfected with Ad.CTLA4Ig via intraarterial ex vivo perfusion were transplanted into streptozotocin-induced diabetic Lewis (LEW; RT1) rats.
  
  
  RESULTS
  Ad.CTLA4Ig transduced grafts combined with a short course of FK506 resulted in indefinitely prolonged survival (>156 days vs. 19.5 days with FK506 alone). CTLA4Ig was predominantly expressed in grafts on day 4. The expression was gradually diminished and was only slightly detectable at day >100. The proliferative responses against BN antigen were remarkably enhanced among recipients with rejected grafts, but the T-cells from tolerant recipients (>100 days) showed poor cytotoxic responses. On adoptive transfer assay, the splenic T-cells of tolerant recipients were able to suppress the rejection of BN, but not third-party Wistar Furth (WF; RT1) hearts in irradiated (480 cGy) LEW recipients. The percentage of CD4CD25 splenic T-cells was significantly increased in tolerant recipients (13.53 +/- 4.06% vs. 6.06 +/- 0.56% in naive rats).
  
  
  CONCLUSIONS
  CTLA4Ig gene transfer to the pancreaticoduodenal allograft combined with a short course of FK506 induces donor-specific tolerance. The mechanism of maintaining tolerance could be explained by development of splenic T suppressor cells.
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Gang
authors.initials: G
authors.lastname: Miao
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ito
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Uchikoshi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Akamaru
authors.forename: Tetsuma
authors.initials: T
authors.lastname: Kiyomoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Komodo
authors.forename: Jinghai
authors.initials: J
authors.lastname: Song
authors.forename: Masumi
authors.initials: M
authors.lastname: Nozawa
authors.forename: Hikaru
authors.initials: H
authors.lastname: Matsuda
mesh_terms: D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D004386:Duodenum / Q000637:transplantation; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D018796:Immunoconjugates / Q000235:genetics* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D016035:Pancreas Transplantation / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D015704:CD4 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D016559:Tacrolimus