Non-human animals having a humanized b-cell activating factor gene

Abstract

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described.

1 . A non-human animal expressing a Baff polypeptide comprising the extracellular portion of a human BAFF protein linked to the intracellular portion of a Baff protein of the non-human animal. 
     
     
         2 . The non-human animal of  claim 1 , wherein the extracellular portion of a human BAFF protein is encoded by exons 3 to 6 of a human BAFF gene. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The non-human animal of  claim 2 , wherein exons 3 to 6 of the human BAFF gene are at least 90% identical with exons 3 to 6 of a human BAFF gene that appears in Table 3. 
     
     
         8 . (canceled) 
     
     
         9 . The non-human animal of  claim 1 , wherein the non-human animal does not detectably express a full-length endogenous Baff protein. 
     
     
         10 . The non-human animal of  claim 1 , wherein the Baff polypeptide is expressed from a humanized Baff gene at an endogenous Baff locus. 
     
     
         11 . The non-human animal of  claim 10 , wherein the humanized Baff gene comprises at least one non-human Baff exon selected from the group consisting of exon 1, exon 2, and full or partial exon 7, of a non-human Baff gene. 
     
     
         12 .- 13 . (canceled) 
     
     
         14 . A non-human animal comprising a humanized Baff gene that comprises one or more exons of a human BAFF gene operably linked to a Baff promoter. 
     
     
         15 . The non-human animal of  claim 14 , wherein the Baff promoter is a non-human animal Baff promoter. 
     
     
         16 . The non-human animal of  claim 14 , wherein the Baff promoter is a human BAFF promoter. 
     
     
         17 . The non-human animal of  claim 14 , wherein the humanized Baff gene comprises exons 3 to 6 of a human BAFF gene. 
     
     
         18 .- 21 . (canceled) 
     
     
         22 . The non-human animal of  claim 17 , wherein exons 3 to 6 of the human BAFF gene are at least 90% identical with exons 3 to 6 of a human BAFF gene that appears in Table 3. 
     
     
         23 . (canceled) 
     
     
         24 . The non-human animal of  claim 14 , wherein the humanized Baff gene comprises a non-human Baff exon selected from the group consisting of exon 1, exon 2, and full or partial exon 7, of a non-human Baff gene. 
     
     
         25 .- 31 . (canceled) 
     
     
         32 . An isolated cell or tissue of the non-human animal of  claim 14 . 
     
     
         33 .- 38 . (canceled) 
     
     
         39 . A method of making a non-human animal that expresses a Baff protein from an endogenous Baff locus, wherein the Baff protein comprises a human sequence, the method comprising the steps of:
 (a) targeting an endogenous Baff gene at an endogenous Baff locus in a non-human embryonic stem (ES) cell with a genomic fragment comprising a human nucleotide sequence that encodes a human BAFF protein in whole or in part;   (b) obtaining a modified non-human ES cell comprising a humanized Baff gene that comprises the human nucleotide sequence of (a) at the endogenous Baff locus; and,   (c) creating a non-human animal using the modified ES cell of (b).   
     
     
         40 . The method of  claim 39 , wherein the human nucleotide sequence comprises exons 3 to 6 of a human BAFF gene. 
     
     
         41 . The method of  claim 39 , wherein the human nucleotide sequence encodes amino acid residues 142 to 285 of a human BAFF protein. 
     
     
         42 . The method of  claim 39 , wherein the non-human animal is a mouse or rat. 
     
     
         43 .- 45 . (canceled) 
     
     
         46 . A method of engrafting human cells into a mouse, the method comprising steps of:
 (a) providing a mouse whose genome comprises a humanized Baff gene that encodes the extracellular portion of a human BAFF protein linked to the intracellular portion of a mouse Baff protein; and   (b) transplanting one or more human cells into the mouse.   
     
     
         47 . (canceled) 
     
     
         48 . The method of  claim 46 , further comprising a step of:
 (c) assaying engraftment of the one or more human cells in the mouse,   
       wherein the step of assaying comprises comparing the engraftment of the one or more human cells to the engraftment in one or more wild-type mice or in one or more mice whose genome does not comprise a humanized Baff gene that encodes the extracellular portion of a human BAFF protein linked to the intracellular portion of a mouse Baff protein. 
     
     
         49 .- 50 . (canceled) 
     
     
         51 . The method of  claim 46 , wherein the human cells are hematopoietic stem cells. 
     
     
         52 . The method of  claim 46 , wherein the human cells are transplanted intravenously, intraperitoneally, or subcutaneously. 
     
     
         53 .- 54 . (canceled) 
     
     
         55 . The non-human animal of  claim 1 , wherein the non-human animal is a rodent. 
     
     
         56 . The non-human animal of  claim 14 , wherein the non-human animal is a rodent.