Antagonizing leukotriene B4 receptors delays cardiac allograft rejection in mice

Background: Allograft rejection is a cellular immunological/inflammatory response that is, in part, directed by potent proinflammatory mediators. This study was designed to test the hypothesis that leukotriene B4 (LTB4) may have a role in graft rejection and that LTB4 receptor antagonists may be clinically useful in the treatment of allograft rejection.

Methods: We evaluated the potent and selective LTB4 receptor antagonist CP-105696 in a murine heterotopic cardiac allograft model with oral dosing daily for 28 days or in an induction protocol (day -1 to day 3).

Results: At a dose of 50 mg/kg/day (28 days), B10.BR (H2k) allografts transplanted into C57Bl/6 (H2b) recipients were significantly protected, as reflected by the mean survival time versus control grafts (27+/-20 days [n=10] vs. 12+/-6 days [n=14]; P=0.0146). Using an induction protocol (day -1 to day 3), CP-105696 at 100 mg/kg/day significantly prolonged allograft survival (33+/-23 days [n=9]; P=0.0026), but CP-105696 at 10 mg/kg/day did not (18+/-16 days [n=8]; P=0.1433). Syngeneic grafts survived indefinitely (n=11). Immunohistological evaluation of allografts at rejection revealed a mononuclear cell infiltrate composed primarily of CD3+ and CD11b+ (Mac-1+) cells, which were infrequent in syngeneic grafts. Allografts from mice treated with CP-105696 at 50 or 100 mg/kg/day demonstrated a selective reduction in beta2-integrin (Mac-1) expression on monocytes/macrophages, as demonstrated by CD11b staining density compared with allograft controls.

Conclusions: The results suggest that LTB4 or other potential ligands for LTB4 receptors may be important mediators of allograft rejection and support the clinical evaluation of LTB4 receptor antagonists in human organ transplantation.