title: Host conditioning and rejection monitoring in hepatocyte transplantation in humans.
abstract: 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.
  
  
  
  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.
  
  
  
  Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy 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 27year 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±48μM (normal 30-119μM) to 854±25μM (treatment goal ≤360μM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Soltys
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Setoyama
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Edgar N
authors.initials: EN
authors.lastname: Tafaleng
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto Gutiérrez
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Fong
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Fukumitsu
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagaya
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sada
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Haberman
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Veysel
authors.initials: V
authors.lastname: Tahan
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dreyzin
authors.affiliation: Division of Vascular and Interventional Radiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Baskin
authors.affiliation: Division of Vascular and Interventional Radiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Crowley
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Mubina A
authors.initials: MA
authors.lastname: Quader
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Melvin
authors.initials: M
authors.lastname: Deutsch
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Squires
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Mugica
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dobrowolski
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: George
authors.initials: G
authors.lastname: Mazariegos
authors.affiliation: Department of Pediatrics, University of British Columbia and Child & Family Research Institute, BC Children's Hospital, Vancouver, Canada.
authors.forename: Rajavel
authors.initials: R
authors.lastname: Elango
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.affiliation: Departments of Pediatrics and Human Genetics, University of Pittsburgh School of Medicine and Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Gerard
authors.initials: G
authors.lastname: Vockley
authors.affiliation: Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, United States; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Roy-Chowdhury
authors.affiliation: Departments of Surgery and Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Marilia
authors.initials: M
authors.lastname: Cascalho
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
authors.affiliation: Departments of Surgery and Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Platt
authors.affiliation: Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address: ira.fox@chp.edu.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D006084:Graft Rejection; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D008099:Liver / Q000528:radiation effects*; D008107:Liver Diseases / Q000628:therapy; D008252:Macaca fascicularis; D008297:Male; D013552:Swine; D019172:Transplantation Conditioning; D014183:Transplantation, Heterologous
keywords: Hepatocyte transplantation; Hepatocyte xenotransplantation; Liver-based metabolic disease; Liver-directed radiation therapy; Phenylketonuria; Rejection risk monitoring