title: Tolerance of rat liver allografts induced by short-term selective immunosuppression combining monoclonal antibodies directed against CD25 and CD54 with subtherapeutic cyclosporine.
abstract: BACKGROUND
  Our purpose was to develop and evaluate protocols for selective immunosuppression after liver transplantation using the monoclonal antibodies (mAbs) NDS-61, directed against the interleukin-2 receptor (CD25), and 1A29, directed against the intercellular adhesion molecule-1 (CD54), in combination with subtherapeutic cyclosporine (CsA).
  
  
  METHODS
  Orthotopic rat liver transplantation (ORLT) was performed in a DA-to-LEW strain combination. Immunosuppression was administered from day 0 to +13. Functional parameters such as survival time, body weight, and serum bilirubin levels were measured and the liver grafts were evaluated histologically.
  
  
  RESULTS
  A stepwise tapering of CsA from 3 to 0.25 mg/kg/day reduced the long-term survival rate. All animals died at a CsA dosage of 0.25 mg/kg/day, which was therefore defined as subtherapeutic. Monotherapy with the anti-CD25 mAb was performed at dosages of 600 and 1800 microg/kg/day. The lower mAb dosage resulted in a long-term survival rate of 12% and was defined as subtherapeutic. The combination therapy of CsA (0.25 mg/kg/day) and anti-CD25 mAb (600 microg/kg/day) produced a synergistic effect and led to a long-term survival rate of 84%. This survival rate was significantly higher than those after either CsA (P<0.005) or anti-CD25 mAb (P<0.001) monotherapy. Both dosages (10 and 30 microg/kg/day) of anti-CD54 mAb monotherapy as well as anti-CD54 mAb combined with a subtherapeutic dosage of CsA were ineffective in preventing acute allograft rejection. The addition of anti-CD54 mAb (30 microg/kg/day) to combined CsA plus anti-CD25 mAb therapy (triple therapy), however, increased the long-term survival rate to 100%. In the triple therapy group there was no rejection process in the liver allografts at any time, and donor-specific tolerance could be shown by donor-specific and third-party heterotopic heart transplantation.
  
  
  CONCLUSIONS
  The synergistic action of subtherapeutic CsA plus anti-CD25 mAb NDS-60 could be demonstrated, whereas anti-CD54 mAb only had a positive effect in a triple therapy group. Triple therapy prevented both acute and chronic rejection and induced donor-specific tolerance.
authors.affiliation: Department of Surgery, University of Wuerzburg, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Gassel
authors.forename: C
authors.initials: C
authors.lastname: Otto
authors.forename: A M
authors.initials: AM
authors.lastname: Gassel
authors.forename: D
authors.initials: D
authors.lastname: Meyer
authors.forename: U
authors.initials: U
authors.lastname: Steger
authors.forename: W
authors.initials: W
authors.lastname: Timmermann
authors.forename: K
authors.initials: K
authors.lastname: Ulrichs
authors.forename: A
authors.initials: A
authors.lastname: Thiede
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008099:Liver / Q000737:chemistry; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D008954:Models, Biological; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D012086:Reoperation; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine