Sulemon Chaudhry1,2, Yojiro Kato1,2, Joshua Weiner1,2, Paula Alonso-Guallart1, Sam Baker3,4, David C Woodland1, Jay H Lefkowitch5, Raimon Duran-Struuck1,6, Hugo P Sondermeijer1, Jonah Zitsman1, Mallory L Sears1, Anette Wu1, Brian Karolewski3, Philipp J Houck7, Mercedes Martinez1,8, Tomoaki Kato2, Megan Sykes1,2,9,10, Adam D Griesemer1,2. 1. Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, USA. 2. Department of Surgery, Columbia University Irving Medical Center, New York, USA. 3. Institute of Comparative Medicine, Columbia University Irving Medical Center, New York, USA. 4. Veterinary Service Center, Stanford University, California, USA. 5. Department of Pathology, Columbia University Irving Medical Center, New York, USA. 6. University of Pennsylvania School of Veterinary Medicine. 7. Department of Anesthesiology, Columbia University Irving Medical Center, New York, USA. 8. Department of Pediatrics, Columbia University Irving Medical Center, New York, USA. 9. Department of Medicine, Columbia University Irving Medical Center, New York, USA. 10. Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, USA.
Abstract
BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survivals are limited by infection, cancer and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on POD 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients was comparable to that previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum IL-6 and IL-2, but peripheral Treg numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.
BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survivals are limited by infection, cancer and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on POD 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients was comparable to that previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum IL-6 and IL-2, but peripheral Treg numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.
Authors: Tatsuo Kawai; A Benedict Cosimi; Siew Lin Wee; Stuart Houser; David Andrews; Hiroshi Sogawa; Joanne Phelan; Svetlan Boskovic; Ognjenka Nadazdin; Gregory Abrahamian; Robert B Colvin; David H Sach; Joren C Madsen Journal: Transplantation Date: 2002-06-15 Impact factor: 4.939
Authors: T Kawai; H Sogawa; M Koulmanda; R N Smith; J J O'Neil; S L Wee; S Boskovic; M Sykes; R B Colvin; D H Sachs; H Auchincloss ; A B Cosimi; D S C Ko Journal: Transplantation Date: 2001-07-27 Impact factor: 4.939
Authors: Ognjenka Nadazdin; Svjetlan Boskovic; Toru Murakami; Georges Tocco; Rex-Neal Smith; Robert B Colvin; David H Sachs; James Allan; Joren C Madsen; Tatsuo Kawai; A Benedict Cosimi; Gilles Benichou Journal: Sci Transl Med Date: 2011-06-08 Impact factor: 17.956
Authors: Andrew B Adams; Matthew A Williams; Thomas R Jones; Nozomu Shirasugi; Megan M Durham; Susan M Kaech; E John Wherry; Thandi Onami; J Gibson Lanier; Kenneth E Kokko; Thomas C Pearson; Rafi Ahmed; Christian P Larsen Journal: J Clin Invest Date: 2003-06 Impact factor: 14.808