A Mixed-chimerism Protocol Utilizing Thymoglobulin and Belatacept Did Not Induce Lung Allograft Tolerance, Despite Previous Success in Renal Allotransplantation

Wiebke Sommer, MD; Jane M. O, MD; Kurt B. Pruner, BSc; Abbas Dehnadi, DVM; Kyu Ha Huh, MD; Kortney A. Robinson, MD; Isabel Hanekamp, PhD; Ivy Rosales, MD; Alison S. Bean, BSc; Josh Paster, BSc; Tetsu Oura, MD; Rex Neal Smith, MD; Robert Colvin, MD; Gilles Benichou, PhD; Tatsuo Kawai, MD; Joren C. Madsen, MD, DPhil; James S. Allan, MD

doi:10.1097/TXD.0000000000001150

Transplantation Direct (Jun 2021)

A Mixed-chimerism Protocol Utilizing Thymoglobulin and Belatacept Did Not Induce Lung Allograft Tolerance, Despite Previous Success in Renal Allotransplantation

Wiebke Sommer, MD,
Jane M. O, MD,
Kurt B. Pruner, BSc,
Abbas Dehnadi, DVM,
Kyu Ha Huh, MD,
Kortney A. Robinson, MD,
Isabel Hanekamp, PhD,
Ivy Rosales, MD,
Alison S. Bean, BSc,
Josh Paster, BSc,
Tetsu Oura, MD,
Rex Neal Smith, MD,
Robert Colvin, MD,
Gilles Benichou, PhD,
Tatsuo Kawai, MD,
Joren C. Madsen, MD, DPhil,
James S. Allan, MD

Affiliations

Wiebke Sommer, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Jane M. O, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Kurt B. Pruner, BSc: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Abbas Dehnadi, DVM
Kyu Ha Huh, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Kortney A. Robinson, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Isabel Hanekamp, PhD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Ivy Rosales, MD: 5 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Alison S. Bean, BSc: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Josh Paster, BSc: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Tetsu Oura, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Rex Neal Smith, MD: 5 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Robert Colvin, MD: 5 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Gilles Benichou, PhD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Tatsuo Kawai, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Joren C. Madsen, MD, DPhil: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
James S. Allan, MD: 1 Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

DOI: https://doi.org/10.1097/TXD.0000000000001150
Journal volume & issue: Vol. 7, no. 6
p. e705

Abstract

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Background. In kidney transplantation, long-term allograft acceptance in cynomolgus macaques was achieved using a mixed-chimerism protocol based on the clinically available reagents, rabbit anti-thymocyte globulin (ATG), and belatacept. Here, we have tested the same protocol in cynomolgus macaques transplanted with fully allogeneic lung grafts. Methods. Five cynomolgus macaques underwent left orthotopic lung transplantation. Initial immunosuppression included equine ATG and anti-IL6RmAb induction, followed by triple-drug immunosuppression for 4 mo. Post-transplant, a nonmyeloablative conditioning regimen was applied, including total body and thymic irradiation. Rabbit ATG, belatacept, anti-IL6RmAb, and donor bone marrow transplantation (DBMT) were given, in addition to a 28-d course of cyclosporine. All immunosuppressant drugs were stopped on day 29 after DBMT. Results. One monkey rejected its lung before DBMT due to AMR, after developing donor-specific antibodies. Two monkeys developed fatal post-transplant lymphoproliferative disorder, and both monkeys had signs of cellular rejection in their allografts upon autopsy. The remaining 2 monkeys showed severe cellular rejection on days 42 and 70 post-DBMT. Cytokine analysis suggested higher levels of pro-inflammatory markers in the lung transplant cohort, as compared to kidney recipients. Conclusion. Although the clinically applicable protocol showed success in kidney transplantation, the study did not show long-term survival in a lung transplant model, highlighting the organ-specific differences in tolerance induction.

Published in Transplantation Direct

ISSN: 2373-8731 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Surgery
Website: http://journals.lww.com/transplantationdirect/Pages/default.aspx

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