title: Hepatocyte growth factor sustains T regulatory cells and prolongs the survival of kidney allografts in major histocompatibility complex-inbred CLAWN-miniature swine.
abstract: BACKGROUND
  Although 12 days of high dose of FK506 permits the induction of tolerance of fully major histocompatibility complex (MHC)-mismatched allogeneic kidneys in MGH-miniature swine, we found that the same dose of FK506 is insufficient to induce such tolerance CLAWN-miniature swine. The CLAWN swine model was therefore chosen to study the potential immunoregulatory effects of human-recombinant hepatocyte growth factor (HGF).
  
  
  METHODS
  Ten CLAWN miniature swine received fully MHC-mismatched kidneys with 12 days (days 0-11) of FK506. Among these 10 recipients, 4 received 7 or 14 days of human-recombinant HGF starting at day 11. Graft function was assessed by daily serum creatinine and biopsies. Immunologic assays, including CD4/CD25 DP and FoxP3+ cells and development of antidonor antibodies, were performed.
  
  
  RESULTS
  Without HGF, all six CLAWN recipients developed severe acute rejection (Cre >9 mg/dL) within 3 weeks of transplantation. In contrast, in the four animals that received HGF for 7 to 14 days, stable renal function was observed for more than 50 days, although all grafts were ultimately rejected by postoperative day 80. Percent FoxP3+ cells in the CD4+CD25+ double positive population (T regulatory cells) in peripheral blood monocyte cells decreased in recipients with FK506 induction monotherapy while no reduction was observed in recipients treated with FK506 and HGF.
  
  
  CONCLUSIONS
  This study demonstrates that in CLAWN swine treated with a dose of FK506 insufficient to induce tolerance across a fully MHC mismatched barrier, a short course of HGF may inhibit acute rejection while maintaining T regulatory cells. To our knowledge, this study provides the first evidence in a large animal transplantation model of HGF's immunoprotective effects.
authors.affiliation: Division of Xenotransplantation Surgery, Frontier Science Research Center, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
authors.forename: Manei
authors.initials: M
authors.lastname: Oku
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Okumi
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sahara
authors.forename: Kentaro
authors.initials: K
authors.lastname: Setoyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Sada
authors.forename: Joseph
authors.initials: J
authors.lastname: Scalea
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tsubouchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000208:Acute Disease; D000818:Animals; D017849:Animals, Inbred Strains; D003404:Creatinine / Q000097:blood; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007518:Isoantibodies / Q000096:biosynthesis; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology; D008285:Major Histocompatibility Complex; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature / Q000235:genetics* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D016559:Tacrolimus / Q000008:administration & dosage; D014184:Transplantation, Homologous
chemical_list: C066855:HGF protein, human; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D003404:Creatinine; D016559:Tacrolimus