Transgenic mice depleted in a mature lymphocytic cell-type

• US 5,591,669 A
• Filed: 05/30/1995
• Issued: 01/07/1997
• Est. Priority Date: 12/05/1988
• Status: Expired due to Term

• Current Assignee: Genpharm International Inc (Bristol-Myers Squibb Company)
• Original Assignee: Genpharm International Inc (Bristol-Myers Squibb Company)
• Inventors: Krimpenfort, Paulus J. A., Berns, Antonius J. M.
• Primary Examiner(s): Chambers, Jasemine C.
• Application Number:
  US08/454,034
• Time in Patent Office: 588 Days
• Field of Search: 800/2, 800/DIG. 1, 800/DIG. 2, 800/DIG. 3, 435/172.3, 435/320.1, 435/317.1, 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 depletion of a mature lymphocytic cell type otherwise naturally occurring in the species from which the transgenic mouse is derived. The phenotype is conferred in the transgenic mouse by a transgene contained in at least the precursor stem cell of the lymphocytic cell type which is depleted. The transgene comprised is a DNA sequence encoding a lymphatic polypeptide variant which inhibits maturation of the lymphocytic cell type.

Claims

1. A transgenic mouse having a phenotype characterized by a disruption of the expression of the Cμ

and Cδ

portions of the endogenous immunoglobulin heavy chain and an absence of plasma B cells producing naturally occurring mouse antibodies, the phenotype being conferred by an immunoglobulin heavy chain targeting transgene introduced into an ES target cell and integrated into somatic and germ cells of the tranegenic mouse or an ancestor thereof by homologous recombination with a cognate endogenous immunoglobulin heavy chain allele to yield a targeted immunoglobulin heavy chain allele which is not expressed, the immunoglobulin heavy chain targeting transgene comprising a stop codon, DNA sequences for identification and selection of ES cells containing the transgene in the targeted allele and DNA sequences of a mouse heavy chain immunoglobulin gene having sufficient sequence homology to recombine with the endogenous allele in said ES target cell.

2. The transgenic mouse of claim 1, wherein the targeted immunoglobulin heavy chain allele further comprises a deletion of nucleotides from the cognate endogenous immunoglobulin heavy chain allele.

3. The transgenic mouse of claim 2 wherein the deletion of nucleotides from the cognate endogenous immunoglobulin heavy chain allele is a deletion of a portion of the variable region.

4. The tranegenic mouse of claim 1, 2, or 3 wherein the immunoglobulin heavy chain targeting transgene consists essentially of DNA sequences homologous to the endogenous immunoglobulin heavy chain allele, sequences for identification and selection of ES cells containing said transgene in said targeted allele, and a mutation which disrupts expression of the targeted allele wherein the mutation is selected from the group consisting of the insertion of sequences comprising a stop codon, the insertion of sequences resulting in a frameshift, and a deletion of a plurality of nucleotides of the endogenous immunoglobulin heavy chain allele.

5. The transgenic mouse of claim 3, wherein the deletion of nucleotides from the cognate endogenous immunoglobulin heavy chain allele comprises a deletion of J segments of the variable region.