Session Name: Tolerance / Immune Deviation
Session Type: Oral Abstract Session
Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:45pm
Presentation Time: 4:27pm-4:39pm
*Purpose: Long-term tolerance of cardiac allografts has been achieved in non-human primates (NHPs) using a mixed chimerism protocol and by co-transplanting a kidney from the same heart and bone marrow donor. In contrast, heart alone recipients rejected in 150-180 days. T cell subset analyses showed greater expansion of regulatory T cells (Treg) in heart/kidney recipients compared to heart alone controls. To achieve tolerance of isolated heart allografts, we added IL-2 and/or anti-IL6R therapy to enhance host Treg activity.
*Methods: Cynomolgus heart alone transplant recipients underwent donor bone marrow transplantation with conditioning that included non-myeloablative total body irradiation, thymic irradiation, equine anti-thymocyte globulin, anti-CD154 mAb, and cyclosporine until post-operative day (POD) 28. Five animals in Group A received low dose IL-2 (1MIU/m2 SC from POD -6 to 5) and IL-6 receptor blockade with tocilizumab (10 mg/kg IV on POD 0, 7, 14, 21, 28, 56, 84, and 112). Seven recipients in Group B, received tocilizumab alone (10 mg/kg IV on POD 0, 7, 14, 21, 28, 56, and 84).
*Results: In Group A, 3/5 animals rejected their allografts at POD 127, 198, and 254 with evidence of acute cellular rejection (ACR), antibody mediated rejection (AMR), and donor specific antibodies (DSA). Two animals died on POD 7 and 11 from sepsis and pancytopenia, respectively. In Group B, 3/7 recipients are ongoing (POD 159 and 110) with one animal over 558 days with no evidence of ACR. 1/7 rejected at POD 169 with ACR3R, pAMR3, and DSA and 3/7 animals died on POD 5, 9, and 65 from a technical failure, sedation complication, and pancytopenia, respectively. Recipients in Group A exhibited an average 15-fold expansion in the percent CD25+FoxP3+ of CD3+CD4+ cells in the periphery compared to an average 3-fold expansion in Group B recipients.
*Conclusions: We have been able to achieve tolerance of an isolated heart allograft using IL-6 receptor blockade along with a regimen of reagents largely available for clinical use. The surprising deleterious effects of low dose IL-2 may be related to its ability to activate alloreactive T cells, despite augmenting Tregs.
To cite this abstract in AMA style:Ahrens K, O JM, Sommer W, Morrissette J, Becerra D, Patel PM, Costa T, Dehnadi A, Hanekamp IM, Allan JS, Benichou G, Madsen JC. IL-6 Receptor Blockade But Not IL-2 Treatment Contributes to Long-Term NHP Cardiac Allograft Survival in Transient Mixed Chimeras [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/il-6-receptor-blockade-but-not-il-2-treatment-contributes-to-long-term-nhp-cardiac-allograft-survival-in-transient-mixed-chimeras/. Accessed August 10, 2022.
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