1. A rodent whose genome comprises a replacement of exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus, and expresses in said rodent a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from a mouse or a rat.
2. The rodent of claim 1, wherein said rodent is a rat.
3. The rodent of claim 2, wherein said humanized SIRP\u03b1 gene comprises exons 1, 5, 6, 7 and 8 of said rodent SIRP\u03b1 gene.
4. The rodent of claim 2, wherein said human SIRP\u03b1 protein comprises the amino acid sequence as set forth in SEQ ID NO: 4.
5. The rodent of claim 4, wherein the extracellular portion of said human SIRP\u03b1 protein comprises amino acid residues 28-362 of said human SIRP\u03b1 protein.
6. The rodent of claim 2, wherein the rat does not express a rat SIRP\u03b1 protein.
7. An isolated rodent cell or tissue whose genome comprises a replacement of exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus, and expresses in said rodent cell or tissue a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from a mouse or a rat.
8. The isolated cell or tissue of claim 7, wherein said rodent is a rat.
9. The isolated cell or tissue of claim 8, wherein the humanized SIRP\u03b1 gene comprises exons 1, 5, 6, 7 and 8 of said rodent SIRP\u03b1 gene.
10. The isolated cell or tissue of claim 8, wherein the cell or tissue does not express a rat SIRP\u03b1 protein.
11. The isolated cell or tissue of claim 8, wherein the cell or tissue is an embryonic stem (ES) cell.
12. A rodent embryo generated from the ES cell of claim 11.
13. A method of making a rodent, the method comprising:
(a) replacing exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus in a rodent ES cell with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus and encodes a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from mouse or rat, thereby obtaining a modified rodent ES cell comprising said humanized SIRP\u03b1 gene;
(b) creating a rodent using the modified ES cell of (a).
14. The method of claim 13, wherein the rodent is rat.
15. The method of claim 14, wherein said humanized SIRP\u03b1 gene comprises exons 1, 5, 6, 7 and 8 of said rodent SIRP\u03b1 gene.
16. The method of claim 14, wherein the extracellular portion of said human SIRP\u03b1 protein comprises amino acid residues 28-362 of SEQ ID NO: 4.
17. A method of engrafting human cells into a rodent, comprising steps of:
(a) providing a rodent whose genome comprises a replacement of exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus and expresses in said rodent a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from a mouse or a rat; and
(b) transplanting one or more human cells into the rodent.
18. The method of claim 17, wherein the rodent is a rat.
19. The method of claim 18, further comprising a step of:
(c) assaying engraftment of the one or more human cells in the rodent.
20. The method of claim 19, 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 rats or in one or more rats whose genome does not comprise said replacement.
21. The method of claim 18, wherein said humanized SIRP\u03b1 gene comprises exons 1, 5, 6, 7 and 8 of said rodent SIRP\u03b1 gene.
22. The method of claim 18, wherein the extracellular portion of said human SIRP\u03b1 protein comprises amino acids 28-362 of SEQ ID NO: 4.
23. The method of claim 18, wherein the human cells are hematopoietic stem cells.
24. The method of claim 18, wherein the human cells are transplanted intravenously, intraperitoneally, or subcutaneously.
25. A method comprising,
(a) providing one or more rodent cells whose genome comprises a replacement of exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus and expresses in said one or more rodent cells a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from a mouse or a rat;
(b) incubating the one or more rodent cells of step (a) with a labeled substrate; and
(c) measuring phagocytosis of the labeled substrate by the one or more rodent cells of step (b).
26. The method of claim 25, wherein said rodent is a rat.
27. The method of claim 26, wherein said humanized SIRP\u03b1 gene comprises exons 1, 5, 6, 7 and 8 of said rodent SIRP\u03b1 gene.
28. The method of claim 26, wherein the substrate is fluorescently labeled or labeled with an antibody.
29. The method of claim 26, wherein the substrate is one or more red blood cells or one or more bacterial cells.
30. A method comprising,
(a) providing a rodent whose genome comprises a replacement of exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus and expresses in said rodent a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from a mouse or a rat;
(b) exposing the rodent to an antigen; and
(c) measuring phagocytosis of the antigen by one or more cells of the rodent.
31. The method of claim 30, wherein said rodent is a rat.
32. The method of claim 31, wherein said humanized SIRP\u03b1 gene comprises exons 1, 5, 6, 7 and 8 of said rodent SIRP\u03b1 gene.
33. The method of claim 31, wherein the step of exposing comprises exposing the rodent to an antigen that is fluorescently labeled.
34. The method of claim 31, wherein the step of exposing comprises exposing the rodent to one or more cells that comprise the antigen.
35. The method of claim 34, wherein the step of exposing comprises exposing the rodent to one or more human cells comprising the antigen or to one or more bacterial cells comprising the antigen.
36. A method of assessing the therapeutic efficacy of a drug targeting human cells, comprising:
providing a rodent whose genome a replacement of exons 2, 3 and 4 of a rodent SIRP\u03b1 gene at an endogenous rodent SIRP\u03b1 locus with exons 2, 3 and 4 of a human SIRP\u03b1 gene to form a humanized SIRP\u03b1 gene, wherein said humanized SIRP\u03b1 gene is operably linked to a rodent SIRP\u03b1 promoter at said endogenous rodent SIRP\u03b1 locus and expresses in said rodent a humanized SIRP\u03b1 protein comprising an extracellular portion of the human SIRP\u03b1 protein encoded by said human SIRP\u03b1 gene and an intracellular portion of the rodent SIRP\u03b1 protein encoded by said rodent SIRP\u03b1 gene, and wherein the rodent is selected from a mouse or a rat;
transplanting one or more human cells into the rodent;
administering a drug candidate to said rodent; and
monitoring the human cells in the rodent to determine the therapeutic efficacy of the drug candidate.
37. The method of claim 36, wherein said rodent is a rat.
38. The method of claim 37, wherein the human cells are cancer cells, and said drug candidate is an anti-cancer drug candidate.
39. The method of claim 36, wherein said drug candidate is an antibody.
40. The method of claim 36, wherein said rodent further comprises human immune cells.
41. The method of claim 40, wherein said drug candidate is a bispecific antibody that binds to an antigen on the human immune cells and an antigen on the transplanted human cancer cells.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A lateral force joint, comprising:
a first plate, in which a through bore (14) with a first diameter is provided, and
a second plate with a first surface, at which a cylinder is formed having a diameter which is adapted to the first diameter so that the cylinder of the second plate positively fits together with the through bore in the first plate for transmitting forces directed perpendicularly to the center line of the cylinder from the first plate to the second plate and vice versa.
2. The lateral force joint according to claim 1,
wherein the first plate further comprises a first bearing bush, which is inserted into the first plate so that the first bearing bush is rotatable around its center line in the plane of the first plate, and
wherein the through bore of the first plate is configured eccentrically in the first bearing bush.
3. The lateral force joint according to claim 2,
wherein the first plate has a first surface, and wherein the first bearing bush has an annular flange, which is configured for abutment with the first surface.
4. The lateral force joint according to claim 3,
wherein the first plate has opposite the first surface a second surface, with which the first bearing bush is substantially flush.
5. The lateral force joint according to claim 1,
wherein the second plate further comprises a circular disc, which is inserted into the second plate so that the circular disc is rotatable around its center line in the plane of the second plate, and
wherein the cylinder of the second plate is formed eccentrically at the circular disc.
6. The lateral force joint according to claim 5,
wherein the circular disc is configured as a second bearing bush.
7. The lateral force joint according to claim 5,
wherein the cylinder is a hollow cylinder with a through opening.
8. The lateral force joint according to claim 7,
wherein the circular disc is an annular perforated disc with a hole, wherein the through opening of the hollow cylinder is aligned with the hole of the annular perforated disc.
9. The lateral force joint according to claim 5,
wherein the second plate has a second surface opposite the first surface, and wherein the second bearing bush has an annular flange, which is configured for abutment with the second surface of the second plate.
10. The lateral force joint according to claim 5,
wherein the second bearing bush is substantially flush with the first surface of the second plate.
11. A spar for a rudder unit, which is configured at least in a joining area to be mounted on an airplane fuselage as a first plate in which a through bore with a first diameter is provided, in order to be connected with a fastening strap mounted on the airplane fuselage and configured as a second plate with a first surface, at which a cylinder is formed having a diameter which is adapted to the first diameter so that the cylinder of the second plate positively fits together with the through bore in the first plate for transmitting forces directed perpendicularly to the center line of the cylinder from the first plate to the second plate and vice versa;
wherein the second plate further comprises a circular disc, which is inserted into the second plate so that the circular disc is rotatable around its center line in the plane of the second plate, and
wherein the cylinder of the second plate is formed eccentrically at the circular disc.