Transgenic mice depleted in mature T-cells and methods for making transgenic mice

• US 5,175,384 A
• Filed: 12/05/1988
• Issued: 12/29/1992
• Est. Priority Date: 12/05/1988
• Status: Expired due to Term

• Current Assignee: Genpharm Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Genpharm Incorporated (Bristol-Myers Squibb Company)
• Inventors: Krimpenfort, Paulus J. A., Berns, Antonius J. M.
• Primary Examiner(s): Weimar, Elizabeth C.
• Assistant Examiner(s): Chambers, Jasemine C.
• Application Number:
  US07/280,218
• Time in Patent Office: 1,485 Days
• Field of Search: 435/172.3, 800/2, 800/DIG. 1-DIG. 3, 935/111
• US Class Current: 800/11
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 2267/0337 Animal models for infectious diseases
• CPC Class Codes: A01K 2267/0381 Animal model for diseases of the hematopoietic system
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination

Abstract

Transgenic mice having a phenotype characterized by the substantial absence of mature T lymphocytes otherwise naturally occurring in said mice. The phenotype is conferred in the transgenic mouse by a transgene contained in at least the precursor stem cell of the T lymphocyte which is depleted. The transgene comprises a DNA sequence encoding a T cell receptor polypeptide variant which inhibits maturation of the T lymphocyte.

Claims

1. A transgenic mouse having a phenotype characterized by the substantial absence of mature T-cells otherwise naturally occurring in said mouse, said phenotype being conferred by a transgene contained in the somatic and germ cells of said mouse, said transgene comprising the Δ

V-TCRβ

DNA fragment which encodes a T-cell antigen receptor polypeptide variant, and said polypeptide variant being incapable of mediating T-cell maturation in said transgenic mouse.

2. A method for producing a transgenic mouse having a phenotype characterized by the substantial absence of mature T-cells otherwise naturally occurring in said mouse, said method comprising:

(a) introducing a transgene into a zygote of a mouse, said transgene comprising the Δ

V-TCRβ

DNA fragment which encodes a T-cell antigen receptor polypeptide variant, said polypeptide variant being incapable of mediating T-cell maturation in said transgenic mouse,

(b) transplanting said zygote into a pseudopregnant mouse.

(c) allowing said zygote to develop to term, and

(d) identifying at least one transgenic offspring containing said transgene.

3. A method for producing a transgenic mouse having a phenotype characterized by the substantial absence of mature T-cells otherwise naturally occurring in said mouse, said method comprising:

(a) introducing a transgene into an embryo of a mouse, said transgene comprising the Δ

V-TCRβ

DNA fragment which encodes a T-cell antigen receptor polypeptide variant, said polypeptide variant being incapable of mediating T-cell maturation in said transgenic mouse.

(b) transplanting said embryo into a pseudopregnant mouse,

(c) allowing said embryo to develop to term, and

(d) identifying at least one transgenic offspring containing said transgene, and

(e) breeding said offspring to form a transgenic mouse having said phenotype.

4. The method of claim 3 wherein said introducing of said transgene into said embryo is by introducing an embryonic stem cell containing said transgene into said embryo.

5. The method of claim 3 wherein said introducing of said transgene into said embryo is by infecting said embryo with a retrovirus containing said transgene.