Antagonizing leukotriene B-4 receptors delays cardiac allograft rejection in mice

Background. Allograft rejection is a cellular immunological/inflammatory re sponse that is, in part, directed by potent proinflammatory mediators. This study was designed to test the hypothesis that leukotriene B-4, (LTB4,) ma y 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 da ily 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 (H2(k)) allografts tra nsplanted into C57B1/6 (H2(b)) 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 sur vival (33+/-23 days [n=9]; P=0,0026), but CP-105696 at 10 mg/ kg/day did no t (18+/-16 days [n=8]; P=0.1433), Syngeneic grafts survived indefinitely (n =11). Immunohistological evaluation of allografts at rejection revealed a m ononuclear 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 red uction in beta(2)-integrin (Mac-l) 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 suppo rt the clinical evaluation of LTB4, receptor antagonists in human organ tra nsplantation.