HEPATOCELLULAR TRANSPLANTATION AND TARGETING GENETIC MARKERS TO HEPATIC CELLS 
deficient Watanabe rabbit. Transplantation of heterologous hepatocytes has been shown 
to effect at least a partial and short-term ameliorization of the systemic 
hypercholesterolemia (Wiederkehr et al, 1990; Wilson et al , 1990), 
Recently published studies by Moscioni et al (1990) described transplantation of 
human hepatocytes into animal models. These authors used athymic rats as recipients for 
human hepatocytes which were attached to collagen-coated microcarriers and injected into 
the peritoneum of the rat. This work demonstrated the feasibility of harvesting human 
hepatocytes, cryopreserving these cells, and transplanting them in a model system. 
D. The Potential for Rejection of Hepatocellular Grafts. 
One of the most profound problems associated with OLT is immune rejection. It is 
likely that there will be an immune response against the transplanted cells which will 
necessitate cyclosporine immunosuppression. Several animal experiments have demonstra- 
ted that a phenotypic response to heterologous hepatocytes requires immunosuppression. 
As described below, we will institute an immunosuppressive protocol identical to that 
used for OLT. It should be noted that there is currently no cross -matching (except for 
ABO compatibility) associated with OLT. In fact the largest retrospective analysis of 
HLA compatibility of donor organs provided no evidence that haplotype or tissue matched 
organs had a better outcome and actually suggested that transplants with fewer 
mismatches have lower survival than mismatched transplants (Markus et al, 1988). 
I 
For several reasons it is possible that rejection may be a less severe problem for 
HCT than OLT. First, isolated hepatocytes, while not entirely free of other hepatic 
I elements, would be relatively depleted of red blood cells, tissue matrix, endothelial 
cells, lymphocytes, and monocyte derived elements (Kupffer cells), many of which may be 
more highly antigenic than the hepatocytes themselves (Lafferty et al, 1983). Second, 
there is evidence from animal experiments that the antigenicity of various cells can be 
decreased by in vitro culture (Lafferty et al, 1976, Bowen et al , 1980, Naj i et al, 
1981). Third, if HCT were to become established as a clinical technique, it might be 
possible to create hepatocyte banks with cryopreserved hepatocytes which could enable 
selective cross matching of donor and host transplantation antigens and even tests for 
rejection potential of the host using mixed lymphocyte -hepatocyte cultures (Bumgardner 
et al, 1990) similar to the mixed lymphocyte cultures used to assess the potential for 
rejection in bone marrow transplantation. 
E. Rationale for use of a marker gene in transplanted hepatocytes. 
The extensive published literature on HCT in various experimental animals and our 
own experiments lead to the conclusion that hepatocyte engraftment can occur under 
! appropriate conditions and that the engrafted cells can continue to express liver 
I specific functions for an indefinite period of time. On the basis of these experimental 
j observations and the demonstrated clinical need for an alternative to OLT in patient's 
I with liver failure, we believe it is appropriate to propose clinical trials of HCT to 
evaluate its potential for ameliorating or reversing hepatic failure or metabolic 
disease , 
Recombinant DNA Research, Volume 14 
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