The International Journal of Artificial Organs / Vol. 20 / no. 4, 1997/ pp.229-233 Liver Assist Devices Immunological consequences of the use of xenogeneic hepatocytes in a bioartificial liver for acute liver failure A.A. te VELDE, L.M. FLENDRIG, N.C.J.J. LADIGES, R.A.F.M. CHAMULEAU Academic Medical Center, University of Amsterdam, Department of Experimental Internal Medicine, Amsterdam - The Netherlands ABSTRACT: The use of cells from xenogeneic origin in a bioartificial liver can have a number of immunological consequences, not only for the cells in the bioartificial liver but also for the patient receiving the bioartificial liver treatment. The impact of these consequences will depend on the im- mune status of the patient receiving bioartificial liver treatment, the duration and frequency of the treatment and on the extent of interaction between the patients blood (or plasma) and the xenogeneic liver cells. In an experimental model we infused rats with a culture supernatant of pig hepatocytes and demonstrated using Western blots and immunohistological techniques that antibodies are raised against the very small amounts of the pig hepatocyte-derived proteins present in the culture medium. Potential problems of bioartificialliver destruction and the possibility of hypersensitivity reactions due to the secretion of xenogeneic proteins into the circulation of the patient are discussed. Because the liver has an important role in the clearance of immune complexes it is concluded that precautions should be taken when (repeated) application of a xenogeneic bioartificialliver in patients with liver fai- lure is considered. (tnt J Artif Organs 1997; 20: 229-33) KEY WORDS: Immunology, Xenogenous, Hepatocytes, Bioartificialliver, Acute liver failure INTRODUCTION In the development of a bioartificial liver for clinical application the use of hepatocytes from xenogeneic origin is the best alternative for human hepatocytes due to the shortage of human donor material and the lack of a good functioning non-tumorigenous human hepatocyte cell line. The best candidate for the supply of hepatocytes is the pig since pig livers can be easily obtained and large numbers of cells can be isolated. One important aspect of the use of cells from xenoge- neic origin in a bioartificial liver is the need for proper immunoisolation to protect the cells in the artificial liver from attack by the cellular (immune cells) and humoral (immunoglobulins) immune system of the patient receiving the bioartificial liver treatment. Recent studies from Nyberg et al (1) and Takahashi et al (2) demonstrate that the potential danger of attack by the patient's immune system can be circumvented using hollow fiber membranes with a molecular cut-off of approximately 100 kD, thereby preven- ting the entering of cells from the immune system (> 10 urn) as well as anti-hepatocyte antibodies (> 150 kD) and complement factors. The authors suggest the use of these hollow fibers because of their permeability to albu- min (67 kD), an important carrier molecule for endogenous toxic substances that have to be transported to the sup- porting liver cells. In addition it is not desirable to have a complete isolation of the cells in the artificial liver from the patients blood or plasma since a number of molecules (e.g. hepatocyte growth factors) produced by the hepa- tocytes in the artificial liver could be of benefit to the patient receiving the bioartificial liver treatment. This issue brings us to the second important aspect of the use of cells from xenogeneic origin in a bioartificial liver namely consequences of the leakage of proteins and other immu- nogenic substances produced by the xenogeneic hepa- tocytes into the circulation of the patient receiving the bioartificial liver treatment. This paper demonstrates that © by Wichtig Editore, 1997 0391-3988/229-05 $03.50/0