LF 15-0195, a novel immunosuppressive agent prevents rejection and induces operational tolerance in a mouse cardiac allograft model.
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.
Zhou
Dejun
D
Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
O'Brien
Catherine
C
Shum
Jeffrey
J
Garcia
Bertha
B
Min
Weiping
W
Jevnikar
Anthony M
AM
Dutartre
Patrick
P
Zhong
Robert
R
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
D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D020123:Sirolimus