Humanized low affinity FCγR mouse cells
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. A mouse lymphocyte having a genome that comprises at least one human low affinity FcγR α-chain gene encoding a human low affinity FcγR α-chain with a polymorphism, wherein the human low affinity FcγR α-chain gene replaces an endogenous low affinity FcγR α-chain gene, and wherein the mouse lymphocyte comprises a functional endogenous FcR γ-chain and functionally expresses the human low affinity FcγR α-chain gene.
2. The mouse lymphocyte of claim 1 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIA α-chain.
3. The mouse lymphocyte of claim 2 , wherein the polymorphism is a 131His polymorphism.
4. The mouse lymphocyte of claim 2 , wherein the polymorphism is a 131Arg polymorphism.
5. The mouse lymphocyte of claim 1 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIB α-chain.
6. The mouse lymphocyte of claim 5 , wherein the polymorphism is a 232Ile polymorphism.
7. The mouse lymphocyte of claim 5 , wherein the polymorphism is a 232Thr polymorphism.
8. The mouse lymphocyte of claim 1 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIIA α-chain.
9. The mouse lymphocyte of claim 8 , wherein the polymorphism is a 158Val polymorphism.
10. The mouse lymphocyte of claim 8 , wherein the polymorphism is a 158Phe polymorphism.
11. The mouse lymphocyte of claim 1 , wherein the mouse lymphocyte is a mouse natural killer (NK) cell, a mouse B cell, or a mouse T cell.
12. A mouse embryonic stem (ES) cell having a genome that comprises at least one human low affinity FcγR α-chain gene encoding a human low affinity FcγR α-chain with a polymorphism, wherein the human low affinity FcγR α-chain gene replaces an endogenous low affinity FcγR α-chain gene, and wherein the mouse ES cell comprises a functional endogenous FcR γ-chain gene.
13. The mouse ES cell of claim 12 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIA α-chain.
14. The mouse ES cell of claim 13 , wherein the polymorphism is a 131His polymorphism.
15. The mouse ES cell of claim 13 , wherein the polymorphism is a 131Arg polymorphism.
16. The mouse ES cell of claim 12 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIB α-chain.
17. The mouse of claim 16 , wherein the polymorphism is a 232Ile polymorphism.
18. The mouse of claim 16 , wherein the polymorphism is a 232Thr polymorphism.
19. The mouse ES cell of claim 12 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIIA α-chain.
20. The mouse ES cell of claim 19 , wherein the polymorphism is a 158Val polymorphism.
21. The mouse ES cell of claim 19 , wherein the polymorphism is a 158Phe polymorphism.
22. A mouse embryo comprising the mouse ES cell of claim 12 .
23. A method of testing an agent comprising an Fc region of a human antibody, the method comprising:
(a) administering an agent comprising an Fc region of a human antibody to a genetically modified mouse whose genome comprises at least one human low affinity FcγR α-chain gene encoding a human low affinity FcγR α-chain with a polymorphism, wherein the human low affinity FcγR α-chain gene replaces an endogenous low affinity FcγR α-chain gene, wherein the mouse comprises a functional endogenous FcR γ-chain and functionally expresses the human low affinity FcγR α-chain gene, wherein the agent comprising an Fc region of a human antibody binds to a target cell in the mouse; and
(b) measuring the cell-mediated immunity elicited by the agent comprising an Fc region of a human antibody in the mouse.
24. The method of claim 23 , wherein the cell-mediated immunity elicited by the agent comprising an Fc region of a human antibody is measured in a blood sample of the mouse.
25. The method of claim 23 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIA α-chain.
26. The method of claim 25 , wherein the polymorphism is a 131His polymorphism.
27. The method of claim 25 , wherein the polymorphism is a 131Arg polymorphism.
28. The method of claim 23 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIB α-chain.
29. The method of claim 28 , wherein the polymorphism is a 232Ile polymorphism.
30. The method of claim 28 , wherein the polymorphism is a 232Thr polymorphism.
31. The method of claim 23 , wherein the human low affinity FcγR α-chain is a low affinity FcγRIIIA α-chain.
32. The method of claim 31 , wherein the polymorphism is a 158Val polymorphism.
33. The method of claim 31 , wherein the polymorphism is a 158Phe polymorphism.