*Purpose: Tolerance of isolated cardiac allografts has never been achieved in NHPs. We investigated whether a cotransplanted, vascularized, donor thymus could induce tolerance of a heart allograft through deletional and/or regulatory mechanisms.

*Methods: MHC-mismatched heart en-bloc thymus allografts were transplanted into 7 thymectomized cynomolgus macaques treated with triple immunosuppression (methylprednisolone, tacrolimus, MMF) for 2 months followed by nonmyeloablative conditioning that included total body irradiation, thymic irradiation, horse anti-thymocyte globulin, anti-CD154 mAb, anti-CD8 mAb, CyA and donor bone marrow transplantation (DBMT) using cryopreserved cells. All drugs were stopped 28 days after DBMT.

*Results: The first adult recipient developed anti-donor antibodies before DBMT and lost its graft 175 days post DBMT to antibody mediated rejection (AMR) without T cell mediated rejection (TCMR). A second adult recipient developed anti-donor antibodies prior to DBMT; but after conditioning and DBMT, has had no evidence of anti-donor antibodies and no evidence of AMR or TCMR on biopsies with a strongly contracting heart 566 days post DBMT. Five juvenile recipients were also transplanted. One died of anemia and infectious complications 47 days post DBMT, one died of PTLD on day 9 post DBMT and one died of airway obstruction on day 75 post DBMT. None of these three showed any signs of allograft rejection. The remaining two juvenile recipients’ allografts stopped beating by 20 weeks post DBMT. Both showed signs of AMR and TCMR. In the juvenile recipients, thymic tissue was found after transplant in only a single recipient, whereas both adult recipients had clearly detectable thymic tissue posttransplant.

*Conclusions: In adult recipients treated with a mixed chimerism protocol, a vascularized donor thymus allograft controlled the cellular but not the humoral anti-donor response leading to prolonged heart allograft survival. However, in juvenile recipients, the same protocol did not offer the same protection, which may be due to the early loss of donor thymus. In adult recipients treated with a mixed chimerism protocol, a vascularized donor thymus allograft controlled the cellular anti-donor response leading to prolonged heart allograft survival. However, it did not achieve B cell tolerance as evidenced by AMR detected by 69 days after transplantation.

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