Genetically modified major histocompatibility complex mice
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsLynn Macdonald, Andrew J. Murphy, Naxin Tu, Cagan Gurer, Vera Voronina, Sean Stevens
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Abstract
The invention provides genetically modified non-human animals that express a humanized MHC II protein (humanized MHC II α and β polypeptides), as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same. Methods of using the genetically modified animals to study various aspects of human immune system are provided.
Claims38
A non-human animal comprising at an endogenous Major Histocompatibility Complex II (MHC II) a gene locus a nucleotide sequence encoding a chimeric human/non-human MHC II α polypeptide,
- wherein a human portion of the chimeric human/non-human MHC II α polypeptide comprises a human MHC II α extracellular domain, and
- wherein the animal expresses a functional MHC II complex on a surface of a cell of the animal.
-9. (canceled)
A non-human animal comprising at an endogenous MHC II β gene locus a nucleotide sequence encoding a chimeric human/non-human MHC II β polypeptide,
- wherein a human portion of the chimeric human/non-human MHC II β polypeptide comprises a human MHC II β extracellular domain, and
- wherein the animal expresses a functional MHC II complex on a surface of a cell of the animal.
-18. (canceled)
A rodent comprising at an endogenous MHC II gene locus a first nucleotide sequence encoding a chimeric human/rodent MHC II α polypeptide and a second nucleotide sequence encoding a chimeric human/rodent MHC II β polypeptide,
- wherein a human portion of the chimeric human/rodent MHC II α polypeptide comprises a human MHC II α extracellular domain and a human portion of the chimeric human/rodent MHC II β polypeptide comprises a human MHC II β extracellular domain, and
- wherein the chimeric human/rodent MHC II α and MHC II β polypeptides form a functional MHC II complex on a surface of a cell of the rodent.
-29. (canceled)
A mouse comprising at an endogenous mouse MHC II locus a first nucleotide sequence encoding a chimeric human/mouse MHC II α polypeptide and a second nucleotide sequence encoding a chimeric human/mouse MHC II β polypeptide,
- wherein a human portion of the chimeric MHC II α polypeptide comprises an extracellular domain derived from an α polypeptide of a human HLA-DR4 protein and the human portion of the chimeric MHC II β polypeptide comprises an extracellular domain derived from a β polypeptide of a human HLA-DR4 protein,
- wherein a mouse portion of the chimeric MHC II α polypeptide comprises transmembrane and cytoplasmic domains of a mouse H-2E α chain and a mouse portion of the chimeric MHC II β polypeptide comprises transmembrane and cytoplasmic domains of a mouse H-2E β chain,
- and wherein the mouse expresses a functional chimeric HLA-DR4/H-2E MHC II complex on a surface of a cell of the mouse.
-34. (canceled)
A method of modifying an MHC II locus of a mouse to express a chimeric human/mouse MHC II complex comprising replacing at the endogenous mouse MHC II locus a nucleotide sequence encoding a mouse MHC II complex with a nucleotide sequence encoding a chimeric human/mouse MHC II complex.
-41. (canceled)
A nucleic acid comprising:
- a first nucleotide sequence encoding a chimeric human/rodent MHC II α polypeptide comprising α1 and α2 domains of a human MHC II α polypeptide operably linked to transmembrane and cytoplasmic domains of a rodent MHC II α polypeptide and/or
- a second nucleotide sequence encoding a chimeric human/rodent MHC II β polypeptide comprising α1 and β2 domains of a human MHC II β polypeptide operably linked to transmembrane and cytoplasmic domains of a rodent MHC II β polypeptide.
An in vitro composition comprising a rodent cell that is an embryonic stem cell or an antigen presenting cell,
- wherein the rodent cell is an embryonic stem cell or an antigen presenting cell,
- wherein the rodent cell comprises a nucleic acid, and
- wherein the nucleic acid comprises:
- a first nucleotide sequence encoding a chimeric human/rodent MHC II α polypeptide comprising α1 and α2 domains of a human MHC II α polypeptide operably linked to transmembrane and cytoplasmic domains of a rodent MHC II α polypeptide and/or
- a second nucleotide sequence encoding a chimeric human/rodent MHC II β polypeptide comprising β1 and β2 domains of a human MHC II α polypeptide operably linked to transmembrane and cytoplasmic domains of a rodent MHC II β polypeptide.
Dependencies are inferred from the claim text.