Wiebke Sommer1,2, Jane M O1, Kurt B Pruner1, Abbas Dehnadi1,2,3,4,5,6,7, Kyu Ha Huh1,3, Kortney A Robinson1,4, Isabel Hanekamp1, Ivy Rosales5, Alison S Bean1, Josh Paster1, Tetsu Oura1, Rex Neal Smith5, Robert Colvin5, Gilles Benichou1, Tatsuo Kawai1, Joren C Madsen1,6, James S Allan1,7. 1. Center for Transplantation Science, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 2. Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. 3. Department of Transplantation Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. 4. Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA. 5. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 6. Division of Cardiac Surgery, Massachusetts General Hospital, Boston, MA. 7. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA.
Abstract
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.
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.
Authors: J D. Mezrich; K Yamada; R S. Lee; K Mawulawde; S L. Houser; M L. Schwarze; M E. Maloney; H C. Amoah; E P. Pillsbury; D H. Sachs; J C. Madsen Journal: J Heart Lung Transplant Date: 2001-02 Impact factor: 10.247
Authors: I Koyama; O Nadazdin; S Boskovic; T Ochiai; R N Smith; M Sykes; H Sogawa; T Murakami; T B Strom; R B Colvin; D H Sachs; G Benichou; A B Cosimi; T Kawai Journal: Am J Transplant Date: 2007-02-07 Impact factor: 8.086
Authors: M Tonsho; S Lee; A Aoyama; S Boskovic; O Nadazdin; K Capetta; R-N Smith; R B Colvin; D H Sachs; A B Cosimi; T Kawai; J C Madsen; G Benichou; J S Allan Journal: Am J Transplant Date: 2015-04-22 Impact factor: 8.086
Authors: J Salman; F Ius; A-K Knoefel; W Sommer; T Siemeni; C Kuehn; I Tudorache; M Avsar; T Nakagiri; G Preissler; R Hatz; M Greer; T Welte; A Haverich; G Warnecke Journal: Am J Transplant Date: 2017-01-24 Impact factor: 8.086
Authors: Pierre-Alain Clavien; Xavier Muller; Michelle L de Oliveira; Philipp Dutkowski; Alberto Sanchez-Fueyo Journal: Lancet Gastroenterol Hepatol Date: 2017-03-28
Authors: Donald E Hricik; Victoria Rodriguez; Jocelyn Riley; Katherine Bryan; Magdalena Tary-Lehmann; Neil Greenspan; Cora Dejelo; James A Schulak; Peter S Heeger Journal: Am J Transplant Date: 2003-07 Impact factor: 8.086
Authors: H Tilg; L Shapiro; E Vannier; D D Poutsiaka; E Trehu; M B Atkins; C A Dinarello; J W Mier Journal: J Immunol Date: 1994-03-15 Impact factor: 5.422