Effects of IL-2 and/ or Anti-IL6R Therapy on Long-term Cardiac Allograft Survival in Non-Human Primates (NHPs)

C. L. Miller, K. J. Ahrens, J. M. O, P. M. Patel, J. A. Morrissette, D. Becerra, T. Costa, A. Dehnadi, I. M. Hanekamp, G. Benichou, J. C. Madsen

Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA

Meeting: 2021 American Transplant Congress

Abstract number: 577

Keywords: Heart, Mixed chimerism, Primates, Tolerance

Topic: Basic Science » Tolerance / Immune Deviation

Session Information

Session Name: Tolerance / Immune Deviation

Session Type: Poster Abstract

Session Date & Time: None. Available on demand.

Location: Virtual

*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 November 21, 2024.

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