BACKGROUND Endocrine allografts are an option for the treatment of endocrine failure. METHODS One lobe of the thyroid was transplanted under the kidney capsule. RESULTS C57BL/10 (H2(b)) thyroids were rejected in naive CBA (H2(k)) mice within 14 days after transplantation. When mice were treated with anti-CD4 monoclonal antibodies (mAb), all grafts survived for more than 60 days. The first grafts still survived after second C57BL/10 or Balb/c (H2(d)) thyroid grafts that were transplanted into the same recipients were rejected acutely, which suggests that the primary grafts were modified under anti-CD4 mAb treatment. To confirm this hypothesis, C57BL/10 thyroid grafts from anti-CD4 mAb-treated mice were retransplanted. All grafts survived in naive mice; this correlated with the overexpression of heme oxygenase-1 (HO-1) in the grafts. Next, an inhibitor of HO-1 (zinc protoporphyrin) or control compound (copper protoporphyrin) was injected intraperitoneally after transplantation of C57BL/10 thyroid grafts into the primary CBA recipients that had been treated with anti-CD4 mAb. The grafts in mice that had been treated with zinc protoporphyrin, but not copper protoporphyrin, were rejected when retransplanted to naive recipients. CONCLUSIONS Overexpression of HO-1 correlated with the protection of fully allogeneic thyroid grafts from rejection when retransplanted into naive recipients.