Purpose: Tolerance of cardiac allografts has been achieved in cynomolgus monkeys for the first time via mixed hematopoietic chimerism and donor kidney co-transplantation, but the mechanism by which a kidney confers tolerance upon a heart remains unclear. Recent studies in mice and with human T cells show that erythropoietin (Epo), a hormone produced by the kidney, prolongs cardiac allograft survival by increasing the ratio of regulatory to effector T cells. Building on this data, we investigated whether exogenously administered Epo could substitute for the donor kidney and enable tolerance induction in non-human primate recipients of isolated heart allografts.

Methods: MHC-mismatched hearts were transplanted into 4 monkeys undergoing nonmyeloablative conditioning that included total body and thymic irradiation, horse ATG, anti-CD154 mAb and a 28-day course of CyA with donor bone marrow transplantation on the day of heterotopic heart transplantation. High dose (10,000 IU/kg) recombinant human Epo was administered three times weekly starting just prior to conditioning and continuing for 280 days.

Results: All recipients had a significant rise in hematocrit and serum epo levels. M9016 developed donor specific antibodies by POD92 and lost allograft contractions on POD100. M8316 developed DSA by day 78 and lost allograft contractions on POD117. M3017's allograft stopped beating on POD71, although its DSA remained negative. All three recipients had ACR3R on autopsy pathology. Previously, the median survival time for heart transplant recipients not treated with Epo was 165 days. In contrast, M6416 received an added single dose of anti-CD8 on POD0. Epo treatment was stopped on POD280 yet its allograft is still contracting strongly over 370 days post-transplant and its most recent biopsy demonstrated tolerance with no signs of acute cellular or humoral rejection and no circulating DSA. All recipients showed an increase in Tregs consistent with previous work in mice and human T cells.

Conclusion: High dose Epo alone does not substitute for donor kidney co-transplantation in achieving cardiac allograft tolerance. However, the combination of CD8⁺ T cell depletion and high dose EPO may allow the induction of cardiac tolerance without the need for kidney cotransplantation.

CITATION INFORMATION: O. J., Robinson K., Sommer W., Pruner K., Paster J., Hanekamp M., Dehnadi A., Rosales I., Smith R., Cravedi P., Heeger P., Benichou G., Madsen J. Effect of Erythropoietin on Cardiac Allograft Survival in Non-Human Primates Am J Transplant. 2017;17 (suppl 3).

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