US 5,675,060 A · Transgenic arthritic mice expressing a T-cell receptor transgene

Abstract

A transgenic animal model for arthritis is disclosed. The arthritic condition results from genetic (or immunologic) manipulations that result in the T cell receptor (TCR) repertoire of the animal being substantially limited relative to the TCR repertoire of a wildtype control animal. The TCR repertoire of the arthritic animal, albeit limited, is functionally viable. In a preferred embodiment, the invention relates to transgenic arthritic mice wherein arthritis results from (1) a transgenic allele which encodes and expresses TCR .alpha. and .beta. subunits that combine in T lymphocytes of the transgenic animal to form a TCR that recognizes an antigen comprising one or more epitopes of an oligopeptide derived from amino acids 41-61 of bovine pancreatic ribonuclease and/or (2) polypeptide arthritogenic self antigens derived from endogenous proteins. The transgenic arthritic mice of the invention provides an animal model which faithfully mimics rheumatoid arthritis and by which human arthritogenic and therapeutic anti-arthritic compositions are evaluated. Also provided herein are therapeutic oligopeptides derived from the variable regions of the TCRs of the transgenes of the invention and/or from the amino acid sequence of proteins comprising endogenous polypeptide arthritogenic antigens.

Claims17

Dependent claims

A transgenic mouse whose somatic and germ line cells contain a transgene encoding a T-cell receptor (TCR), wherein said TCR has an alpha-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.5 and a beta subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.7, wherein the expression of said transgene results in said mouse having chronic inflammation and deformation of one or more synovial joints.

A method for determining the anti-arthritic potential of a composition comprising the steps of:

(a) administering a known dose of said composition to a first transgenic mouse before inflammation, irremediable joint destruction and limb deformation have occurred;
(b) detecting the onset of irremediable joint destruction and limb deformation in said first transgenic mouse;
and
(c) comparing the time of onset of irremediable joint destruction and limb deformation in said first transgenic mouse to the time of onset of irremediable joint destruction and limb deformation in a second transgenic arthritic mouse which has not been exposed to said composition,
wherein said first transgenic mouse and said second transgenic mouse both contain and express a transgene encoding a T-cell receptor (TCR), wherein said TCR has an alpha-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.5 and a beta-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.7 and wherein expression of said transgene results in a statistically significant delay in the time of onset of irremediable joint destruction and limb deformation in said first transgenic mouse relative to the time of onset of irremediable joint destruction and limb deformation in said second transgenic arthritic mouse indicates the anti-arthritic potential of said composition.

2 more elements

A method for determining the anti-arthritic potential of a composition comprising the steps of:

(a) administering a known dose of said composition to a first transgenic mouse before irremediable joint destruction and limb deformation has occurred;
(b) monitoring the extent of irremediable joint destruction and limb deformation in said first transgenic mouse;
and
(c) comparing the extent of irremediable joint destruction and limb deformation in said first transgenic mouse to the extent of irremediable joint destruction and limb deformation in a second transgenic mouse which has not been exposed to said composition,
wherein said first transgenic mouse and said second transgenic mouse both contain and express a transgene encoding a T-cell receptor (TCR), wherein said TCR has an alpha-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.5 and a beta-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.7 and wherein expression of said transgene results in a statistically significant decrease in the extent of irremediable joint destruction and limb deformation in said first transgenic arthritic mouse relative to the extent of irremediable joint destruction and limb deformation in said second transgenic mouse indicates the anti-arthritic potential of said composition.

2 more elements

A method for determining the arthritogenic potential of composition comprising the steps of:

(a) administering a known dose of said composition to a first KRN transgenic mouse before irremediable joint destruction and limb deformation has occurred;
(b) detecting the onset of irremediable joint destruction and limb deformation in said first KRN transgenic mouse;
and
(c) comparing the time of onset of irremediable joint destruction and limb deformation in said first KRN transgenic mouse to the time of onset of irremediable joint destruction and limb deformation in a second KRN transgenic mouse which has not been exposed to said composition,
wherein said first transgenic mouse and said second transgenic mouse both contain and express a transgene encoding a T-cell receptor (TCR), wherein said TCR has an alpha-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.5 and a beta-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.7 and wherein expression of said transgene results in a statistically significant delay in the time of onset of irremediable joint destruction and limb deformation in said second KRN transgenic mouse relative to the time of onset of irremediable joint destruction and limb deformation in said first KRN transgenic mouse indicates the arthritogenic potential of composition.

2 more elements

A method for determining the arthritogenic potential of a composition comprising the steps of:

(a) administering a known dose of said composition to a first KRN transgenic mouse before irremediable joint destruction and limb deformation has occurred;
(b) monitoring the extent of irremediable joint destruction and limb deformation in said first KRN transgenic mouse;
and
(c) comparing the extent of irremediable joint destruction and limb deformation in said first KRN transgenic mouse to the extent of irremediable destruction and limb deformation in a second KRN transgenic mouse which has been exposed to said composition,
wherein said first transgenic mouse and said second transgenic mouse both contain and express a transgene encoding a T-cell receptor (TCR), wherein said TCR has an alpha-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.5 and a beta-subunit comprising a variable region having an amino acid sequence as shown in SEQ ID NO.7 and wherein a statistically significant increase in the extent of irremediable joint destruction and limb deformation in said first KRN transgenic mouse relative to the extent of irremediable joint destruction and limb deformation in said second KRN transgenic mouse indicates the arthritogenic potential of said composition.

2 more elements

Dependencies are inferred from the claim text.

Transgenic arthritic mice expressing a T-cell receptor transgene

Life of this patent

Transgenic arthritic mice expressing a T-cell receptor transgene

Life of this patent

Abstract

Claims17