Method of producing a mouse suitable for engraftment, differentiation and proliferation of heterologous cells, mouse produced by this method and use of the mouse

Abstract

The present invention provides an immunodeficient mouse (NOG mouse) suitable for engraftment, differentiation and proliferation of heterologous cells, and a method of producing such a mouse. This mouse is obtained by backcrossing a C.B-17-scid mouse with an NOD/Shi mouse, and further backcrossing an interleukin 2-receptor γ-chain gene-knockout mouse with the thus backcrossed mouse. It is usable for producing a human antibody and establishing a stem cell assay system, a tumor model and a virus-infection model.

1 . A method of producing a human antibody comprising immunizing with an antigen a mouse produced by a method comprising backcrossing a mouse B with a mouse A, wherein said mouse A is a mouse obtained by backcrossing a C.B-17-scid mouse with an NOD/Shi mouse; and where IN said mouse B is an interleukin 2-receptor γ chain gene knockout mouse, wherein said mouse produced by the method does not express the interleukin 2-receptor γ chain, has an enhanced engraftment capacity of heterologous cells relative to a NOD/Shi-scid mouse, has neither functional T-cells noR functional B-cells, exhibits reduced macrophage function relative to a NOD/Shi-scid mouse, exhibits no NK cells or NK cell activity, and exhibits reduced dendritic function relative to a NOD/Shi-scid mouse, and retains human T-cells and B-cells.  
     
     
         2 . A method of producing an antibody-producing cell line which produces a human antibody, comprising: 
 immunizing with an antigen a mouse produced by a method comprising backcrossing a mouse B with a mouse A, wherein said mouse A is a mouse obtained by backcrossing a C.B-17-scid mouse with an NOD/Shi mouse; and wherein said mouse B is an interleukin 2-receptor γ chain gene knockout mouse, wherein said mouse produced by the method does not express the interleukin 2-receptor γ chain, has an enhanced engraftment capacity of heterlogous cells relative to a NOD/Shi-scid mouse, has neither functional T-cells nor functional B-cells, exhibits reduced macrophage function relative to a ND/Shi-scid mouse, exhibits no NK cells or NK cell activity, and exhibits reduced dendritic function relative to a NOD/Shi-scid mouse, and retains a human T-cell and B-cell;    collecting from the mouse a cell which produced the antibody against the antigen; and    establishing a cell line of the cell.    
     
     
         3 . A method of screening an anticancer agent comprising screening the anticancer agent using a mouse produced by a method comprising backcrossing a mouse B with a mouse A, wherein said mouse A is a mouse obtained by backcrossing a C.B-17-scid mouse with an NOD/Shi mouse; and wherein said mouse B is an interleukin 2-receptor γ chain gene knockout mouse, wherein said mouse produced by the method does not express the interleukin 2-receptor γ chain, has an enhanced engraftment capacity of heterologous cells relative to a NOD/Shi-scid mouse, has neither functional T-cells nor functional B-cells, exhibits reduced macrophage function relative to NOD/Shi-scid mouse, exhibits no NK cells or NK cell activity, and exhibits reduced dendritic function relative to a NOD/Shi-scid mouse, and retains a human tumor cell.  
     
     
         4 . The method of screening an anticancer agent according to  claim 3 , wherein the mouse retains a human tumor cell derived from HTLV-1 leukemia.  
     
     
         5 . The method of screening an anticancer agent according to  claim 3  or  4 , wherein the mouse retains the human tumor cell at an auricle thereof.  
     
     
         6 . A method of producing a product mouse which retains a human tumor cell comprising transplanting human tumor cells to a mouse produced by a method comprising backcrossing a mouse B with a mouse A, wherein said mouse A is a mouse obtained by backcrossing a C.B-17-scid mouse with an NOD/Shi mouse; and wherein said mouse B is an interleukin 2-receptor γ chain gene knockout mouse, wherein said mouse produced by the method does not express the interleukin 2-receptor γ chain, has an enhanced engraftment capacity of heterologous cells relative to a NOD/Shi-scid mouse, has neither functional T-cells nor functional B-cells, exhibits reduced macrophage function relative to a NOD/Shi-scid mouse, exhibits no NK cells or NK cell activity, and exhibits reduced dendritic function relative to a NOD/Shi-scid mouse.  
     
     
         7 . The method according to  claim 6 , wherein the human tumor cell is derived from HTLV-1 leukemia.  
     
     
         8 . The method according to  claim 5  or  6 , wherein the human tumor cell is transplanted at an auricle of the mouse.  
     
     
         9 . A method of screening an antiviral agent, wherein the method is carried out using a mouse produced by a method comprising backcrossing a mouse B with a mouse A, wherein said mouse A is a mouse obtained by backcrossing a C.B-17-scid mouse with an NOD/Shi mouse; and wherein said mouse B is an interleukin 2-receptor γ chain gene knockout mouse, wherein said mouse produced by the method does not express the interleukin 2-receptor γ chain, has an enhanced engraftment capacity of heterologous cells relative to a NOD/Shi-scid mouse, has neither functional T-cells nor functional B-cells, exhibits reduced macrophage function relative to a NOD/Shi-scid mouse, exhibits no NK cells or NK cell activity, and exhibits reduced dendritic function relative to a NOD/Shi-scid mouse, and retains a T-cell infected with a T-tropic (T-cell affinity) virus as well as a macrophage-tropic virus.  
     
     
         10 . The method of screening an antiviral agent, according to  claim 9 , wherein the mouse retains a T-cell infected with HIV.  
     
     
         11 . The method of screening an antiviral agent according to  claim 9 , wherein the mouse retains a T-cell infected with HTLV-1.