title: Induction of donor-specific tolerance using superagonistic CD28 antibody in rat renal allografts: regulatory T-cell expansion before engraftment may be important.
abstract: BACKGROUND
  We hypothesized that a superagonistic monoclonal antibody specific for CD28 (CD28SA), which expands regulatory T cells (Tregs) in vivo, would prevent acute rejection and prolong the survival of renal allograft.
  
  
  METHODS
  We examined whether CD28SA treatment induce donor-specific tolerance using our established rat renal allograft model (Wistar-Lewis).
  
  
  RESULTS
  All control rats died within 13 days because of severe azotemia with marked destruction of graft tissue. In contrast, recipients treated with a triple injection of CD28SA (days -3, 0, and 3) showed good preservation of graft histology and function, with considerable infiltration of Tregs into the allografts; 92% of recipients survived for more than 100 days, and 77% survived by the day of harvest at 180 days. These long-surviving recipients received secondary heterotopic bicardiac allografts from both donor-matched Wistar and third-party Brown Norway rats simultaneously 120 days after kidney transplantation, and seven of eight (87.5%) rats exhibited donor-specific tolerance, accepting the Wistar heart, but acutely rejecting the Brown Norway heart. Interestingly, a single injection of CD28SA 3 days before (day -3), but not 3 days after (day 3), transplantation also induced donor-specific tolerance in some recipients. We then performed adoptive transfer of nonspecific CD4+CD25+ Tregs, purified from CD28SA-treated Lewis rats, with simultaneous injection of hepatocyte growth factor (500 μg/kg/day, intravenously). The treatment induced significant prolongation of graft survival (P<0.0001 vs. control group), and five of eight (62.5%) recipients survived until the day of harvest at 180 days with successful induction of donor-specific tolerance.
  
  
  CONCLUSIONS
  We have established a novel therapeutic approach for inducing donor-specific tolerance in rats with renal allografts.
authors.affiliation: Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan. uro004@poh.osaka-med.ac.jp
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Hayahito
authors.initials: H
authors.lastname: Nomi
authors.forename: Teruo
authors.initials: T
authors.lastname: Inamoto
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
authors.forename: Tomas
authors.initials: T
authors.lastname: Hounig
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Ichimaru
authors.forename: Naokazu
authors.initials: N
authors.lastname: Ibuki
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Takanobu
authors.initials: T
authors.lastname: Ubai
authors.forename: Yoji
authors.initials: Y
authors.lastname: Katsuoka
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007518:Isoantibodies / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D007737:Kynurenine / Q000097:blood; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051381:Rats; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007518:Isoantibodies; D007737:Kynurenine