Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: In non-human primates (NHPs), a mixed chimerism-based conditioning protocol results in kidney transplant tolerance and combined kidney and heart allograft tolerance. Previous work showed that treatment with recombinant erythropoietin (rEPO), a kidney-produced hormone, prolongs murine cardiac allograft survival associated with regulatory T cell (Treg) expansion. Herein, we tested the hypothesis that high-dose EPO treatment can replace the kidney transplant to induce cardiac allograft tolerance in a mixed-chimerism NHP model.
*Methods: Ten cynomolgus monkeys underwent heterotopic heart transplant and received non-myeloablative total body irradiation, thymic irradiation, equine anti-thymocyte globulin (50 mg/kg IV on days -2, -1, and 0), anti-CD154 mAb (20 mg/kg IV on days 0 and 2 and 10 mg/kg IV on days 5, 7, 9, and 12), and cyclosporine (daily for 28 days). Group A (n=2) received high-dose rEPO (10,000 IU subcutaneously 3 times weekly for 280 days) and anti-CD8 mAb (aCD8) (20 mg/kg IV on day 0). Group B (n=3) received EPO and aCD8 (5 mg/kg IV on days -1 and 2). Group C (n=3) received rEPO alone and Group D (n=2) received aCD8 alone (20 mg/kg IV on day 0).
*Results: One recipient in Group A died of CMV infection at day 44 while the other recipient continues to have a functioning allograft at day 1,104 with no evidence of antibody mediated rejection (AMR) or acute cellular rejection (ACR). 3/3 recipients in Group B died at day 28, 33, and 44 from cardiac infarction, CMV infection, and post-transplant lymphoproliferative disorder respectively. 3/3 animals in Group C had graft failure at days 71, 100, and 117 with evidence of ACR and AMR on pathology. 2/2 recipients in Group D died at days 28 and 32 of CMV infection. The tolerant recipient exhibited a 20.3% expansion in peripheral Tregs compared to an average 14.0% expansion in rEpo-treated recipients and a 2.6% expansion in heart alone controls.
*Conclusions: Treatment with high-dose EPO and aCD8 has resulted in one of the first examples of cardiac allograft tolerance in a fully MHC-mismatched NHP pair. These data provide the basis for further studies aimed at investigating the effects of EPO and CD8 T cell depletion on prolonged heart graft survival. Employing a delayed tolerance induction strategy may reduce the complication rate.
To cite this abstract in AMA style:Ahrens K, O JM, Sommer W, Morrissette J, Becerra D, Patel PM, Dehnadi A, Costa T, Hanekamp IM, Allan JS, Cravedi P, Heeger PS, Benichou G, Madsen JC. Cardiac Allograft Tolerance Can be Achieved in Non-Human Primates via Transient Mixed Hematopoietic Chimerism and Erythropoietin Administration [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/cardiac-allograft-tolerance-can-be-achieved-in-non-human-primates-via-transient-mixed-hematopoietic-chimerism-and-erythropoietin-administration/. Accessed April 19, 2021.
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