Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts

SPECIFIC AIMSBilirubin has been considered a natural waste product of the body. However, several epidemiological studies have shown that individuals with slightly above normal levels of serum bilirubin have less incidence of heart disease than those with low levels, suggesting that bilirubin may have beneficial effects, possibly related to its potent antioxidant properties. We tested our hypothesis that biliverdin, a precursor of bilirubin, has a salutary effect in suppressing alloimmune responses and prolonging cardiac allograft survival.PRINCIPAL FINDINGS1. Biliverdin administration induces donor-specific tolerance to cardiac allograftsWe first asked whether biliverdin has a beneficial effect in transplantation. Untreated control B6AF1 (H-2k/d,b) mouse recipients rejected DBA/2 (H-2d) cardiac allografts in a median of 11.5 days (n=6; Fig. 1⤻ a). In contrast, administration of biliverdin twice (every 12 h) or three (every 8 h) times per day at 50 μmol/kg/dose (n=6 per group) significantly increased graft...