Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys.
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.
Yang
Hongji
H
Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
Chen
Gang
G
Kanai
Nobuyuki
N
Shum
Jeffrey
J
Garcia
Bertha
B
Huang
Xuyan
X
Min
Weiping
W
Luo
Yigang
Y
Dutartre
Patrick
P
Zhong
Robert
R
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
D006146:Guanidines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; C434185:LF 150195