title: Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys.
abstract: BACKGROUND
  LF 15-0195 is a novel, more potent, and less toxic analogue of 15-deoxyspergualin, an antibiotic used as an immunosuppressive agent to prevent rejection of organ transplants. This study was undertaken to determine whether LF 15-0195 monotherapy would prevent renal allograft rejection in a nonhuman primate model.
  
  
  METHODS
  In the study groups, recipients received LF 15-0195 monotherapy at doses of 0.065 mg/kg per day (group 2, n=4), 0.13 mg/kg per day (group 3, n=4), or 0.2 mg/kg per day (group 4, n=4), administered subcutaneously, on postoperative days 0 to 14.
  
  
  RESULTS
  Group 1 consisted of untreated control recipients, all of which developed advanced graft rejection after surviving for an average of 6.5+/-0.6 days. LF 15-0195 treatment significantly prolonged graft survival in groups 2, 3, and 4, to 20+/-20 days, 49+/-5 days, and 39+/-4 days, respectively. Animals in groups 3 and 4 demonstrated no evidence of rejection during LF 15-0195 treatments. The animals maintained stable renal function for 2 weeks after LF 15-0195 withdrawal but gradually developed rejection at 5 to 6 weeks. Pathologic studies demonstrated that vascular graft rejection was attenuated in LF 15-0195-treated allografts, compared with control specimens. These groups also demonstrated transient reductions in lymphocyte counts during treatment, which returned to normal levels 2 weeks after LF 15-0195 withdrawal. Total serum concentrations of IgM and IgG decreased by a mean of 20.4% and a mean of 31.4%, respectively, at the end of LF 15-0195 treatment (postoperative day 14). LF 15-0195 did not significantly alter thrombocyte counts or hemoglobin levels. Necropsy studies showed no evidence of drug toxicity in the heart, liver, spleen, intestines, stomach, or colon.
  
  
  CONCLUSIONS
  LF 15-0195 monotherapy significantly prolonged renal allograft survival in monkeys. These encouraging data suggest that this novel agent may be of future value in clinical transplantation.
authors.affiliation: Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Hongji
authors.initials: H
authors.lastname: Yang
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kanai
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shum
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Xuyan
authors.initials: X
authors.lastname: Huang
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
authors.forename: Yigang
authors.initials: Y
authors.lastname: Luo
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutartre
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000818:Animals; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D006146:Guanidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D009994:Osmolar Concentration; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D006146:Guanidines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; C434185:LF 150195