HEPATOCELLULAR TRANSPLANTATION AND TARGETING GENETIC MARKERS TO HEPATIC CELLS 
dorsal fascia (Jirtle et al , 1980). Most reports describe only short-term correction 
of the phenotype. It has been argued that the decrease in bilirubin is not related to 
hepatocyte engraftment and is an artifact due to reticuloendothelial blockage (Woods 
and Parbhoo, 1981) or enzyme replacement from the absorbed graft. The experiment of 
Vroemen et al (1986) in which hyperbilirubinemia was corrected by HCT into the spleen 
but then partially recurred following splenectomy seems to establish clearly a 
relationship between engraftment and the phenotypic response. A second model for HCT 
is the analbuminemic rat in which transplantation of hepatocytes has been shown to 
increase serum albumin (Demetriou, 1986a; 1986b; 1986c). A third model involves the 
rescue of chemically hepatectomized animals by HCT. HCT has been shown to improve 
survival of animals with hepatic failure induced by N-galactosamine (Makowka et al , 
1980; Grundmann et al, 1986), dimethylnitrosamine (Sutherland et al , 1977; Contini et 
al, 1983), or surgery (Minato et al, 1984; Demetriou et al, 1988). HCT has also been 
reported to ameliorate experimentally induced hepatic failure in dogs (Toledo -Pereyra 
et al, 1982; Sommer et al, 1979). Some of these reports suggest that engraftment is not 
necessary and that a hepato tropic factor in the graft is responsible for the effect 
(Baiimgartner et al, 1983; Makowka et al, 1981; Grundmann et al, 1986; Contini et al, 
1983; Minato, 1984). Failures of this technique have also been discussed (tenBerg et 
al, 1985). HCT has been reported in a variety of larger animals including rabbits 
(Wiederkehr et al, 1990), dogs (Benito et al, 1989; Martin et al, 1987; Kasai et al, 
1987), and pigs (Nordlinger et al, 1985). Two published reports have suggested clinical 
benefit to HCT in cirrhotic dogs (Benito et al, 1989; Martin et al, 1987). 
The major deficiency of many animal studies is the lack of histological markers for 
transplanted cells and the consequent inability to document engraftment. Hepatocytes, 
presumably remnants of transplanted cells, have been seen in venules and sinusoids of 
the liver after transplantation into the portal vein (Sutherland et al, 1977). 
Unequivocal histological evidence of engraftment has been obtained in heterotopic sites 
including fat pads (Jirtle and Michalopoulos , 1982), spleen (Mito et al, 1979; Woods et 
al, 1982; Minato et al, 1984; Fogli et al, 1987; Vroemen et al, 1985; 1986; Fuller et 
al, 1983), and fascia (Jirtle et al, 1980). Several studies have demonstrated 
engraftment and survival of hepatocytes in the peritoneum attached to microcarriers 
(Demetriou et al, 1986a; 1986b; 1986c; 1988); solid supports (Anderson et al, 1989); 
Gelfoam (Thompson et al, 1989); or bioabsorbable polymers (Vacant! et al, 1988). 
Engraftment of hepatocytes has been reported to be enhanced by partial hepatectomy 
(Jirtle and Michalopoulous , 1982; Gupta et al, 1987; Vroemen et al, 1988a), 
immunosuppression (Mataset al, 1976; Demetriou et al, 1986a), allogeneic bone marrow 
transplantation (Nakamura et al, 1986); angiogenesis factor (Thompson et al , 1988); or 
collagen IV coated supports (Anderson et al, 1989). 
j Experiments in the laboratory of Dr. Savio Woo have explored HCT in mice using 
j hepatocytes from transgenic animals which express a human AAT gene (Shen et al, 1987) 
I or an E. coli B-galactosidase (B-gal) gene under the control of the liver-specific AAT 
I promoter (Ponder et al, 1991). When cells from these transgenic animals were 
1 transplanted into normal recipients, secretion of human AAT into the blood served as a 
1 quantifiable marker for hepatocyte engraftment and function. Specific antibodies 
against human AAT were used to detect the transgene product by western blot or 
Recombinant DNA Research, Volume 14 
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