Background: We have achieved tolerance of cardiac allografts in Cynomolgus monkeys for the first time by using a mixed chimerism-based conditioning protocol and by co-transplanting a donor kidney. The mechanism by which a kidney confers tolerance upon a heart is unclear. To gain mechanistic insight and at the same time develop a clinically relevant tolerance protocol, we investigated whether a vascularized donor thymus could substitute for the donor kidney.

Methods:MHC-mismatched heart en bloc thymus allografts were transplanted into 3 thymectomized Cynomolgus macaques treated triple immunosuppression (Methylprednisolon, Tacrolimus, MMF) for 2 months followed by a 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 marrow. All drugs were stopped 29 days after DBMT.

Results: The first recipient developed anti-donor B cell antibodies before DBMT (posttransplant day 38) and lost its graft 175 days post DBMT due to humoral rejection with no histologic evidence of cellular rejection. The second recipient developed failure to thrive and died 47 days post DBMT due to infectious complications without histologic evidence of allograft of rejection. The third monkey is ongoing and exhibits a strong contracting allograft 201 post DBMT. Its most recent biopsy showed C4d negative staining and no histologic signs of rejection. Importantly, all three heart allografts exhibited absent or minimal cellular rejection on surveillance biopsies and autopsy specimens. Anti-donor responses IFNy-ELISPOT and MLR assays showed no increase in cellular anti-donor responses posttransplant.

Conclusion: A vascularized donor thymus allograft appears to control the cellular but not humoral anti-donor response to a co-transplanted cardiac allograft in recipients treated with a mixed chimerism protocol. This suggests that an element intrinsic to the kidney is responsible for its tolerogenicity and that a B cell depleting agent may be required to achieve long term heart en bloc thymus allograft survival.

CITATION INFORMATION: Sommer W., O. J., Pruner K., Paster J., Hanekamp M., Dehnadi A., Rosales I., Smith R., Colvin R., Benichou G., Allan J., Madsen J. Heart En Bloc Thymus Cotransplantation in NHPs Controls Cellular but Not Humoral Alloreactivity Am J Transplant. 2017;17 (suppl 3).

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