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The only curative treatment for enzymatic deficiency such as Ornithine transcarbamylase (OTC) deficiency is liver transplantation. We have studied hepatocyte transplantation as alternative therapy in spfash mouse, the animal mode of OTC deficiency. Hepatocytes were obtained from C57BL/6J strain mice (normal OTC activity). About 2 x 10(6) hepatocytes in 0.1 ml were injected in the spleen of recipient mouse. We then studied: ammonemia, urinary orotate, spleen OTC activity, liver OTC activity, histological presence of hepatocytes in the spleen, immunohistochemical OTC staining in liver and spleen hepatocytes. In syngeneic hepatocyte transplantation (C57 > C57) functional transplanted hepatocytes were found in the spleen over 5 months after transplantation. In allogeneic transplantation (C57 > spfash) without immunosuppression, hepatocytes were rejected in 3 days. With cyclosporine immunosuppression, hepatocyte survived 12 days and showed OTC activity. A few transplanted hepatocytes with OTC activity migrated from spleen of liver. Metabolic disorder were not corrected. This technically easy method (compared to whole liver transplantation) demonstrated 2 problems: reject in allogeneic transplantation and the small amount of injected enzyme.

In some strain combinations of rats, orthotopic liver transplantation (OLT) permits long-term donor-specific survival of fully allogeneic kidney, heart or skin grafts. The difficulties encountered in the clinical situation to obtain tolerance of small-bowel transplantation (SBT), in spite of massive non-specific immunosuppression, led us to study possible liver-induced tolerance in SBT. Inbred DA (RTIa) and PVG (RT1c) rats were used respectively as donors and recipients and divided in two groups: group 1: SIT alone (n = 6); group 2: combined OLT/SBT (n = 6). SIT was performed 17 days after OLT. No immunosuppressive treatment was given to the recipients. Biopsies of small-bowel grafts were performed in both groups at various times after small bowel engraftment. All animals in group 1 showed evidence of acute rejection of the graft between days 6 and 9 post-graft. The histologic pattern of rejection associated lamina propria (LP) mononuclear cell infiltration, crypt lesions and villous atrophy at the end-point of rejection. In group 2, long-term survival (> 100 days) of small bowel grafts was achieved in five of the six animals in spite of strong mononuclear cell infiltration in the LP, which peaked two months after small bowel grafting but then disappeared partially. This striking mononuclear cell infiltrate contrasted with only minor epithelial damage. These data demonstrate that liver grafting can enhance the survival of a small-bowel graft from the same donor in a rat model. Histological findings show that an intense immunological reaction takes place within liver-induced tolerated small-bowel grafts.

The aim of a combined liver/intestinal transplantation experimental model in rats is the study of the liver-induced tolerance of a solid, vascularized and highly immunogenic organ. Animals. Inbred Lewis rats were divided in two syngenic groups: 1. small intestine grafting (n = 10); 2. combined liver/intestinal grafting (n = 10). Intestinal grafting was performed 15 days after liver transplantation. Results. 10/10 animals were alive after 60 days in the first group and 7/10 in the second. Intestinal graft viability was good and 3 intestinal biopsies were done without any complication in each animal. All samples were histologically normal. Our study using syngenic animals prove that combined liver/intestinal transplantation is technically possible and reliable.

An experimental study was carried out in rats to evaluate the outcome of small bowel anastomoses in the presence of peritonitis with and without protection by a polyglactin 910 mesh. One hundred and thirty rats were operated. 1) Thirty small bowel anastomoses were performed in a sterile environment to evaluate the morbidity and mortality due to the surgical procedure itself. All these animals had an uneventful course. 2) Forty anastomoses were performed in a septic environment without protection. Twelve rats died immediately after the procedure. Six rats developed an anastomotic fistula and 22 had an uneventful course. 3) Sixty anastomoses were performed in a septic environment and protected by a polyglactin 910 mesh. Seventeen rats died immediately after the procedure. There were no anastomotic disruptions. Seventeen rats had an uneventful course, and 28 (65%) developed stenosis of the anastomosis. Protection of small bowel anastomoses by a polyglactin 910 mesh appears to effectively prevent disruptions (no anastomotic fistulae or locoregional infections were recorded). However, the mesh is responsible for an intense inflammatory reaction, that often results in intestinal obstruction.