Humanized FcgR mice
Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion of the endogenous low affinity FcγR locus, and wherein the mouse is capable of expressing a functional FcRγ-chain. Genetically modified mice are described, including mice that express low affinity human FcγR genes from the endogenous FcγR locus, and wherein the mice comprise a functional FcRγ-chain. Genetically modified mice that express up to five low affinity human FcγR genes on accessory cells of the host immune system are provided.
1. An isolated mouse lymphocyte comprising a contiguous human nucleotide sequence that encodes at least two α-chains of an FcγR selected from FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB, and a combination thereof; wherein the contiguous human nucleotide sequence replaces mouse FcγR sequences in a mouse FcγR locus, and wherein the mouse lymphocyte comprises a functional FcR γ-chain gene.
2. The lymphocyte of claim 1 , wherein the at least two α-chains are human FcγRIIA α-chain and human FcγRIIIA α-chain.
3. The lymphocyte of claim 2 , wherein the human FcγRIIIA α-chain comprises a phenylalanine at amino acid position 158.
4. The lymphocyte of claim 2 , wherein the human FcγRIIIA α-chain comprises a valine at amino acid position 158.
5. The lymphocyte of claim 1 , wherein the at least two α-chains are selected from human FcγRIIB α-chain, human FcγRIIC α-chain, human FcγRIIIB α-chain, and a combination thereof.
6. The lymphocyte of claim 1 , wherein the lymphocyte is a B cell comprising a human nucleotide sequence that encodes a human CD20 protein, and wherein the lymphocyte does not express an endogenous mouse CD20 protein.
7. The lymphocyte of claim 1 , wherein the lymphocyte is an NK cell that expresses a human FcγRIIIA α-chain.
8. The lymphocyte of claim 1 , wherein the lymphocyte is a monocyte, a macrophage, a polymorphonuclear (PMN) cell, a basophil, an eosinophil, or a T cell, and wherein the lymphocyte expresses a human FcγRIIA α-chain.
9. The lymphocyte of claim 1 , wherein the lymphocyte is an NK cell.
10. The NK cell of claim 9 , wherein the NK cell expresses an α-chain of human FcγRIIC.
11. The NK cell of claim 9 , wherein the NK cell expresses an α-chain of human FcγRIIIA.