Non-human vertebrate comprising human liver cells transplanted therein and method for producing the same
AssigneeCentral Institute for Experimental Animals
InventorHiroshi Suemizu
Life of this patent
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Abstract
This invention provides a non-human vertebrate exhibiting a higher human liver cell growth rate, a higher human liver cell replacement rate, and higher histological-physiological human reproducibility than existing non-human vertebrates comprising the human liver transplanted therein and a method for producing such non-human vertebrate. Specifically, the method for producing a transgenic non-human vertebrate comprising human liver cells transplanted therein comprises transplanting human liver cells in a non-human vertebrate that has impaired or lowered immune reactions against humans in the presence of human IL-6 in vivo.
Claims10
A method for producing a transgenic immunodeficient mouse expressing a human Interleukin-6 (hIL-6) transgene and comprising human liver cells transplanted therein, the method comprising:
- providing an immunodeficient mouse expressing hIL-6 wherein the somatic and germ cells of the immunodeficient mouse comprise a constitutively-active transgene encoding hIL-6 and the endogenous mouse IL-6 gene is not disrupted;
- inducing liver injury in the immunodeficient mouse expressing the hIL-6 transgene;
- and
- transplanting human liver cells into the liver of the immunodeficient mouse expressing the hIL-6 transgene,
- wherein 70% or more mouse liver cells are replaced with human liver cells such that human liver tissue is produced that comprises a portal triad composed of an interlobular artery, interlobular vein, and interlobular bile duct and functions of the human liver, and the liver injury is induced by one or more of the methods selected from the group consisting of (i) to (iv):
- (i) administering a suicide substrate to the immunodeficient mouse expressing the hIL-6 transgene, wherein the liver cells of the immunodeficient mouse expressing the hIL-6 transgene express thymidine kinase, and wherein the suicide substrate is a guanosine analog;
- (ii) expressing a urokinase-type plasminogen activator gene in the liver cells of the immunodeficient mouse expressing the hIL-6 transgene;
- (iii) impairing the fumarylacetoacetate hydrolase (Fah) gene of the immunodeficient mouse expressing the hIL-6 transgene;
- and
- (iv) administering any of the compounds (a) to (e) below:
- (a) carbon tetrachloride;
- (b) acetaminophen;
- (c) d-galactosamine;
- (d) thioacetamide;
- and (e) anti-Fas antibody.
Dependencies are inferred from the claim text.