The vast majority of patients awaiting organ transplantation have end-stage chronic liver disease secondary Ito cirrhosis. Hepatocyte transplantation has several important advantages over organ transplantation and was recently shown to prolong the survival and improve the physiologic abnormalities associated with Icirrhosis and end-stage liver disease in rodents. The number of human livers available for hepatocyte isolation and later transplantation, however, is limited. One possible solution to the human donor availability issue is transplantation of hepatocytes from pigs. Two major concerns regarding the use of porcine Ihepatocytes in man relate to the degree to which xenogeneic hepatocytes can restore normal liver physiology to patients with liver dysfunction and the immunological response to liver cells or their products. Preliminary studies indicate that immunosuppression may not be needed to improve the survival or function of allogeneic rat or pig hepatocytes transplanted in cirrhotic rats. However, specific antibody and cellular immune responses to pig hepatocytes vary by species and the specific physiologic compatibility and function of pig liver proteins in man is unknown. We now propose to extend our observations in a primate model that will serve as a prelude to clinical application.
The aims of this proposal are: 1) To test the degree to which porcine hepatocyte transplantation can improve liver function in cirrhotic non-human primates; 2) To examine whether pig hepatocytes are susceptible to rejection mediated by ant!-swine antibodies and test whether the primate immune response to porcine hepatocytes is significantly different in cirrhotic versus non-cirrhotic recipients; and 3) To determine whether porcine hepatocyte transplantation leads to systemic complications that include a) immune complex formation, b) activation of the coagulation/complement system and c) immune sensitization that may preclude later allotransplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049472-05
Application #
7163048
Study Section
Special Emphasis Panel (ZRG1-SSS-W (01))
Program Officer
Kraemer, Kristy A
Project Start
2003-07-01
Project End
2008-05-31
Budget Start
2007-01-01
Budget End
2008-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$258,109
Indirect Cost
Name
University of Nebraska Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Soltys, Kyle A; Setoyama, Kentaro; Tafaleng, Edgar N et al. (2017) Host conditioning and rejection monitoring in hepatocyte transplantation in humans. J Hepatol 66:987-1000
Chen, Yong; Li, Yanfeng; Wang, Xia et al. (2015) Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes. Stem Cell Reports 5:22-30
Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro et al. (2014) A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. Int J Radiat Oncol Biol Phys 88:404-411
Ding, Jianqiang; Yannam, Govardhana R; Roy-Chowdhury, Namita et al. (2011) Spontaneous hepatic repopulation in transgenic mice expressing mutant human ?1-antitrypsin by wild-type donor hepatocytes. J Clin Invest 121:1930-4
Soltys, Kyle A; Soto-Gutierrez, Alejandro; Nagaya, Masaki et al. (2010) Barriers to the successful treatment of liver disease by hepatocyte transplantation. J Hepatol 53:769-74
Basma, Hesham; Soto-GutiƩrrez, Alejandro; Yannam, Govardhana Rao et al. (2009) Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 136:990-9
Yamanouchi, Kosho; Zhou, Hongchao; Roy-Chowdhury, Namita et al. (2009) Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology 49:258-67
Kawashita, Yujo; Guha, Chandan; Moitra, Rituparna et al. (2008) Hepatic repopulation with stably transduced conditionally immortalized hepatocytes in the Gunn rat. J Hepatol 49:99-106
Fox, Ira J; Strom, Stephen C (2008) To be or not to be: generation of hepatocytes from cells outside the liver. Gastroenterology 134:878-81
Nagata, Hideo; Nishitai, Ryuta; Shirota, Chiyoe et al. (2007) Prolonged survival of porcine hepatocytes in cynomolgus monkeys. Gastroenterology 132:321-9

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