Host conditioning and rejection monitoring in hepatocyte transplantation in humans

Kyle A. Soltys, Kentaro Setoyama, Edgar N. Tafaleng, Alejandro Soto Gutiérrez, Jason Fong, Ken Fukumitsu, Taichiro Nishikawa, Masaki Nagaya, Rachel Sada, Kimberly Haberman, Roberto Gramignoli, Kenneth Dorko, Veysel Tahan, Alexandra Dreyzin, Kevin Baskin, John J. Crowley, Mubina A. Quader, Melvin Deutsch, Chethan Ashokkumar, Benjamin L. Shneider & 15 others Robert H. Squires, Sarangarajan Ranganathan, Miguel Reyes-Mugica, Steven F. Dobrowolski, George Mazariegos, Rajavel Elango, Donna B. Stolz, Stephen C. Strom, Gerard Vockley, Jayanta Roy-Chowdhury, Marilia Cascalho, Chandan Guha, Rakesh Sindhi, Jeffrey L. Platt, Ira J. Fox

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background & Aims Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10 Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27 year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343 ± 48 μM (normal 30–119 μM) to 854 ± 25 μM (treatment goal ≤360 μM) after transplant (36% decrease; p <0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900 μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. Conclusions Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. Lay summary Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Original languageEnglish (US)
Pages (from-to)987-1000
Number of pages14
JournalJournal of Hepatology
Volume66
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Hepatocytes
Transplantation
Liver
Transplants
Immunologic Monitoring
Inborn Genetic Diseases
Radiation
Primates
Acute Liver Failure
Phenylalanine
Immunosuppression
Tissue Donors
Phenylketonurias
Survival
Graft Rejection
Graft Survival
Mitosis
Heterografts
Haplorhini
Urea

Keywords

  • Hepatocyte transplantation
  • Hepatocyte xenotransplantation
  • Liver-based metabolic disease
  • Liver-directed radiation therapy
  • Phenylketonuria
  • Rejection risk monitoring

ASJC Scopus subject areas

  • Hepatology

Cite this

Soltys, K. A., Setoyama, K., Tafaleng, E. N., Soto Gutiérrez, A., Fong, J., Fukumitsu, K., ... Fox, I. J. (2017). Host conditioning and rejection monitoring in hepatocyte transplantation in humans. Journal of Hepatology, 66(5), 987-1000. https://doi.org/10.1016/j.jhep.2016.12.017

Host conditioning and rejection monitoring in hepatocyte transplantation in humans. / Soltys, Kyle A.; Setoyama, Kentaro; Tafaleng, Edgar N.; Soto Gutiérrez, Alejandro; Fong, Jason; Fukumitsu, Ken; Nishikawa, Taichiro; Nagaya, Masaki; Sada, Rachel; Haberman, Kimberly; Gramignoli, Roberto; Dorko, Kenneth; Tahan, Veysel; Dreyzin, Alexandra; Baskin, Kevin; Crowley, John J.; Quader, Mubina A.; Deutsch, Melvin; Ashokkumar, Chethan; Shneider, Benjamin L.; Squires, Robert H.; Ranganathan, Sarangarajan; Reyes-Mugica, Miguel; Dobrowolski, Steven F.; Mazariegos, George; Elango, Rajavel; Stolz, Donna B.; Strom, Stephen C.; Vockley, Gerard; Roy-Chowdhury, Jayanta; Cascalho, Marilia; Guha, Chandan; Sindhi, Rakesh; Platt, Jeffrey L.; Fox, Ira J.

In: Journal of Hepatology, Vol. 66, No. 5, 01.05.2017, p. 987-1000.

Research output: Contribution to journalArticle

Soltys, KA, Setoyama, K, Tafaleng, EN, Soto Gutiérrez, A, Fong, J, Fukumitsu, K, Nishikawa, T, Nagaya, M, Sada, R, Haberman, K, Gramignoli, R, Dorko, K, Tahan, V, Dreyzin, A, Baskin, K, Crowley, JJ, Quader, MA, Deutsch, M, Ashokkumar, C, Shneider, BL, Squires, RH, Ranganathan, S, Reyes-Mugica, M, Dobrowolski, SF, Mazariegos, G, Elango, R, Stolz, DB, Strom, SC, Vockley, G, Roy-Chowdhury, J, Cascalho, M, Guha, C, Sindhi, R, Platt, JL & Fox, IJ 2017, 'Host conditioning and rejection monitoring in hepatocyte transplantation in humans', Journal of Hepatology, vol. 66, no. 5, pp. 987-1000. https://doi.org/10.1016/j.jhep.2016.12.017
Soltys KA, Setoyama K, Tafaleng EN, Soto Gutiérrez A, Fong J, Fukumitsu K et al. Host conditioning and rejection monitoring in hepatocyte transplantation in humans. Journal of Hepatology. 2017 May 1;66(5):987-1000. https://doi.org/10.1016/j.jhep.2016.12.017
Soltys, Kyle A. ; Setoyama, Kentaro ; Tafaleng, Edgar N. ; Soto Gutiérrez, Alejandro ; Fong, Jason ; Fukumitsu, Ken ; Nishikawa, Taichiro ; Nagaya, Masaki ; Sada, Rachel ; Haberman, Kimberly ; Gramignoli, Roberto ; Dorko, Kenneth ; Tahan, Veysel ; Dreyzin, Alexandra ; Baskin, Kevin ; Crowley, John J. ; Quader, Mubina A. ; Deutsch, Melvin ; Ashokkumar, Chethan ; Shneider, Benjamin L. ; Squires, Robert H. ; Ranganathan, Sarangarajan ; Reyes-Mugica, Miguel ; Dobrowolski, Steven F. ; Mazariegos, George ; Elango, Rajavel ; Stolz, Donna B. ; Strom, Stephen C. ; Vockley, Gerard ; Roy-Chowdhury, Jayanta ; Cascalho, Marilia ; Guha, Chandan ; Sindhi, Rakesh ; Platt, Jeffrey L. ; Fox, Ira J. / Host conditioning and rejection monitoring in hepatocyte transplantation in humans. In: Journal of Hepatology. 2017 ; Vol. 66, No. 5. pp. 987-1000.
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abstract = "Background & Aims Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15{\%} of irradiated segments in immunosuppressed monkeys preconditioned with 10 Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27 year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343 ± 48 μM (normal 30–119 μM) to 854 ± 25 μM (treatment goal ≤360 μM) after transplant (36{\%} decrease; p <0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900 μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. Conclusions Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. Lay summary Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.",
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TY - JOUR

T1 - Host conditioning and rejection monitoring in hepatocyte transplantation in humans

AU - Soltys, Kyle A.

AU - Setoyama, Kentaro

AU - Tafaleng, Edgar N.

AU - Soto Gutiérrez, Alejandro

AU - Fong, Jason

AU - Fukumitsu, Ken

AU - Nishikawa, Taichiro

AU - Nagaya, Masaki

AU - Sada, Rachel

AU - Haberman, Kimberly

AU - Gramignoli, Roberto

AU - Dorko, Kenneth

AU - Tahan, Veysel

AU - Dreyzin, Alexandra

AU - Baskin, Kevin

AU - Crowley, John J.

AU - Quader, Mubina A.

AU - Deutsch, Melvin

AU - Ashokkumar, Chethan

AU - Shneider, Benjamin L.

AU - Squires, Robert H.

AU - Ranganathan, Sarangarajan

AU - Reyes-Mugica, Miguel

AU - Dobrowolski, Steven F.

AU - Mazariegos, George

AU - Elango, Rajavel

AU - Stolz, Donna B.

AU - Strom, Stephen C.

AU - Vockley, Gerard

AU - Roy-Chowdhury, Jayanta

AU - Cascalho, Marilia

AU - Guha, Chandan

AU - Sindhi, Rakesh

AU - Platt, Jeffrey L.

AU - Fox, Ira J.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Background & Aims Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10 Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27 year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343 ± 48 μM (normal 30–119 μM) to 854 ± 25 μM (treatment goal ≤360 μM) after transplant (36% decrease; p <0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900 μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. Conclusions Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. Lay summary Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

AB - Background & Aims Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10 Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27 year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343 ± 48 μM (normal 30–119 μM) to 854 ± 25 μM (treatment goal ≤360 μM) after transplant (36% decrease; p <0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900 μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. Conclusions Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. Lay summary Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

KW - Hepatocyte transplantation

KW - Hepatocyte xenotransplantation

KW - Liver-based metabolic disease

KW - Liver-directed radiation therapy

KW - Phenylketonuria

KW - Rejection risk monitoring

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