Using mTOR Inhibitor Nanoimmunotherapy to Induce Cardiac Allograft Tolerance in Non-Human Primates
1MGH, Boston, MA, 2Emory University, Atlanta, GA, 3Icahn School of Medicine at Mount Sinai, New york, NY, 4Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, 5Icahn School of Medicine at Mount Sinai, New York, NM, 6Icahn School of Medicine at Mount Sinai, New York, NY, 7Massachusetts General Hospital - Harvard Medical S, Marblehead, MA, 8Mount Sinai School of Med, New York, NY, 9Massachusetts General Hospital, Boston, MA
Meeting: 2022 American Transplant Congress
Abstract number: 169
Keywords: Heart/lung transplantation, Tolerance
Topic: Basic Science » Basic Science » 12 - Immunosuppression & Tolerance: Preclinical & Translational Studies
Session Information
Session Name: Immunosuppression and Tolerance: Preclinical and Translational Studies
Session Type: Rapid Fire Oral Abstract
Date: Sunday, June 5, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 5:50pm-6:00pm
Location: Hynes Ballroom A
*Purpose: Though tolerance of kidney allografts has been consistently achieved using a mixed-chimerism model, cardiac allografts remain resistant to tolerance induction. Lipoprotein-based nanobiologics loaded with a mammalian target of rapamycin inhibiting prodrug (mTOR inhibiting nanobiologics, mTORi-NBs) inhibit trained immunity and promote graft infiltrating M2-macrophages, which provides a favorable local milieu for tolerance induction. In this study, we evaluate the ability of mTORi-NBs to induce tolerance in a cardiac allograft model in NHPs.
*Methods: Six NHPs underwent simultaneous heterotopic heart and bone marrow transplantation for mixed-chimerism induction. Group A (n=3) was conditioned with 3 Gy total body irradiation (TBI), 7 Gy thymic irradiation (TI), ATGAM, anti-CD40L monoclonal antibody on days 0, 2, 5,7, 9, and 12 post-bone-marrow transplant (pBMTx), and cyclosporine until day 28 pBMTx. Group B recipients (n=3) underwent the same conditioning regimen with the addition of mTORi-NBs at a dose of 0.15 mg/kg on days 2, 5, 12, 19, and 26 pBMTx. Group B donors were also treated with a single dose of mTORi-NBs two days before transplant.
*Results: In group A, all allografts had end-stage rejection by day 175 pBMTx with a mean duration of lymphocyte chimerism of 74 days. The first recipient in group B developed durable full chimerism and mild graft versus host disease (GVHD) which resolved after a course of steroids and cyclosporine. After resolution of his GVHD, his graft continued beating strongly with no evidence of rejection through day 239 pBMTx. The second and third recipients received half-dose (1.5 Gy) TBI and both allografts are contracting strongly at days 317 and 72 pBMTx, though the second recipient had some evidence of rejection at day 212 pBMTx. The mean duration of lymphocyte chimerism in Group B was 158 days.
*Conclusions: Preliminary studies suggest that adding mTORi-NB nanoimmunotherapy to a mixed chimerism protocol prolongs both donor lymphocyte chimerism and heart graft survival in NHPs, even when reducing pre-operative TBI.
To cite this abstract in AMA style:
O JM, Patel PM, Teunissen AJ, Miller CL, Costa T, Momodu M, Muldoon D, Dehnadi A, Hanekamp IM, Pothula V, Sanchez-Tarjuelo R, Prevot G, Mulder WJ, Allan J, Ochando J, Madsen J. Using mTOR Inhibitor Nanoimmunotherapy to Induce Cardiac Allograft Tolerance in Non-Human Primates [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/using-mtor-inhibitor-nanoimmunotherapy-to-induce-cardiac-allograft-tolerance-in-non-human-primates/. Accessed May 9, 2025.« Back to 2022 American Transplant Congress