title: LF 15-0195, a novel immunosuppressive agent prevents rejection and induces operational tolerance in a mouse cardiac allograft model.
abstract: BACKGROUND
  LF 15-0195 (LF) is a new analogue of 15-deoxyspergualin (DSG) that is less toxic and more potent than DSG. The present study was undertaken to determine (1). the dose response of LF monotherapy, (2). its ability to induce tolerance, and (3) its interaction with cyclosporine (CsA), FK 506 (FK), and rapamycin (RAPA).
  
  
  METHODS
  Varying doses of LF were administered to determine dose-dependent effects on graft survival in a C57BL/6 to BALB/c heterotopic heart allograft mouse model. Transplanting-donor and third-party skin grafts into long-term survivors were used to assess the tolerance status. CsA, FK, and RAPA were combined with LF to determine their interactive effects on graft survival.
  
  
  RESULTS
  The efficacy and toxicity of LF was dose dependent. High-dose LF monotherapy (>2 mg/kg) induced donor-specific operational tolerance, but it was associated with high mortality. Simultaneous administration of high-dose calcineurin inhibitors (CsA FK) prevented tolerance induced by LF. In contrast, a short course of LF combined with a subtherapeutic dose of CsA FK achieved indefinite survival of C57/BL6 cardiac allografts. RAPA and LF had a synergistic effect in induction of tolerance.
  
  
  CONCLUSIONS
  The efficacy and toxicity of LF were dose dependent. A short course of LF significantly reduced the requirement of CsA or FK to prevent rejection. RAPA and LF had synergy in induction of tolerance. These data indicate that LF may be a promising agent that warrants further studies in nonhuman primate models of transplantation.
authors.affiliation: Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Dejun
authors.initials: D
authors.lastname: Zhou
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Brien
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shum
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutartre
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006146:Guanidines / Q000627:therapeutic use*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000627:therapeutic use; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D020123:Sirolimus