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

Biliverdin, a product of heme oxygenase‐1 (HO‐1) enzymatic action, is converted into bilirubin, which has been considered a waste product in the past. We now show that administration of biliverdin has a salutary effect in organ transplantation. A brief course of treatment with biliverdin leads to long‐term survival of H‐2 incompatible heart allografts. Furthermore, those recipients harboring long‐surviving (>100 days) allografts were tolerant to donor antigens indicated by the acceptance of second donor strain hearts but not third‐party grafts. Treatment with biliverdin decreased intragraft leukocyte infiltration and inhibited T cell proliferation. Likely related to tolerance induction, biliverdin interferes with T cell signaling by inhibiting activation of nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF‐κB), two transcription factors involved in interleukin‐2 (IL‐2) transcription and T cell proliferation, as well as suppressing Th1 interferon‐γ (IFN‐γ) production in vitro. These findings support the potential use of biliverdin, a natural product, in transplantation and other T cell mediated immune disorders.