Session Name: Tolerance / Immune Deviation
Session Date & Time: None. Available on demand.
*Purpose: Cardiac allograft tolerance in NHPs has been achieved by our group using a mixed chimerism model with allogeneic bone marrow transplant after non-myeloablative conditioning but not without kidney co-transplantation. Transplantation of the heart alone results in graft rejection within 150-180 days. Our results suggest that the ability of the kidney to confer tolerance on the co-transplanted heart relates to its ability to induce the expansion/activation of host regulatory T cells (Tregs). We investigated whether IL-2 and/ or anti-IL6R therapy could substitute for the kidney and induce cardiac allograft tolerance by augmenting Tregs.
*Methods: Sixteen cynomolgus NHPs underwent heart and donor bone marrow transplant with mixed chimerism conditioning including total body and thymic irradiation, ATGAM, anti-CD154 mAb, and cyclosporine until post-operative day (POD) 28. Recipients in Group A (n=5) received low dose IL-2 therapy (1M IU/m2 SC, POD -6 to 5) and an anti-IL6R mAb (tocilizumab, 10 mg/kg IV, POD 0, 7, 14, 21, 28, 56, 84, 112). Recipients in Group B (n=11) received tocilizumab alone (10 mg/kg IV, POD 0, 7, 14, 21, 28, 56, 84).
*Results: In Group A, 3/5 recipients rejected at POD 127, 198, and 254 with acute cellular rejection (ACR), antibody mediated rejection (AMR), and donor specific antibodies (DSA). 2/5 died due to sepsis (POD11) or technical complications (POD7). In Group B, 4/11 recipients are ongoing, of which 2 are >430 days post-transplant without ACR. 1/11 rejected at POD 621 but only after donor skin transplant on POD 526. 1/11 failed to develop chimerism and rejected at POD 169. Graft failure/ death occurred in 5/11 due to technical or sedation complications (POD3, POD5 [n=2], POD9) and pancytopenia (POD65). Group A recipients exhibited an average 15-fold expansion in percent CD25+FoxP3+ of peripheral CD3+CD4+ cells compared to 3-fold expansion in Group B.
*Conclusions: Despite its ability to promote Tregs, combined IL-2/ aIL6R treatment failed to achieve long-term allograft survival. We surmise that this was due to IL-2 stimulation of alloreactive memory T cells. In contrast, aIL6R mAb treatment alone achieved long-term allograft survival (>1 year) off immunosuppression in 3 recipients and represents a promising strategy towards clinical cardiac allograft tolerance.
To cite this abstract in AMA style:Miller CL, Ahrens KJ, O JM, Patel PM, Morrissette JA, Becerra D, Costa T, Dehnadi A, Hanekamp IM, Benichou G, Madsen JC. Effects of IL-2 and/ or Anti-IL6R Therapy on Long-term Cardiac Allograft Survival in Non-Human Primates (NHPs) [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/effects-of-il-2-and-or-anti-il6r-therapy-on-long-term-cardiac-allograft-survival-in-non-human-primates-nhps/. Accessed June 11, 2021.
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