asialo-gm1-ganglioside and retrorsine

The animal model with humanized liver is useful for testing drug metabolism and toxicity in preclinical studies. A mouse model has been reported in which the liver was repopulated more than 90% with human hepatocytes; however, in the rat, the target is far from being reached. In this study, we attempt to develop a humanized liver model with an immunodeficient rat.. Rag1 knockout rats were treated with neonatal thymectomy. At 3 and 4 weeks of age, they were injected with hepatotoxin retrorsine; 2 weeks after, the animals were subjected to 70% partial hepatectomy and transplanted with immature human hepatocytes via portal vein. The recipients were also treated with anti-asialo GM1 antibody weekly from the day before transplantation and were injected with FK506 every 3 days after transplantation.. In Rag1 knockout rats, B lymphocytes were deleted almost completely in peripheral blood. However, T and natural killer (NK) lymphocytes were kept present. When they were treated additionally with neonatal thymectomy for T-lymphocyte deletion and suppressed neutralized NK lymphocytes with anti-asialo GM1, B, T, and NK cells in lymphocytes were reduced to very low levels of 0.75%, 1.58%, and 0.26%, respectively. After transplanting human donor hepatocytes into retrorsine-treated recipient livers, at week 3 the human cell-derived hepatic colonies were expanded in the recipient liver and the liver repopulation rate with human hepatocytes reached approximately 17%. The human hepatocyte-specific genes, albumin, CYP3A4, CYP2C18, and CYP2C9, also could be detected in the recipient rat.. It is possible to generate a chimera animal with humanized liver in a novel severely immunodeficient rat model.

Topics: Animals; Antibodies; Aryl Hydrocarbon Hydroxylases; B-Lymphocytes; Cell Proliferation; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; G(M1) Ganglioside; Genes, RAG-1; Genetic Markers; Hepatectomy; Hepatocytes; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver; Liver Regeneration; Liver Transplantation; Models, Animal; Pyrrolizidine Alkaloids; Rats, Sprague-Dawley; Rats, Transgenic; RNA, Messenger; Serum Albumin; Serum Albumin, Human; Species Specificity; T-Lymphocytes; Tacrolimus; Thymectomy; Time Factors; Transplantation Chimera