Model Description

Tg197 mice develop spontaneous arthritis characterized by swelling of the ankles, hind limb distortion, impaired movement and progressive weight loss, closely resembling the human pathology. Symptoms start to develop at 3-4 weeks of age with established arthritis at 6-7 weeks of age and fully exacerbated pathology by 10 weeks of age.

     
Figure 1: Representative images depicting the progression of arthritis in Tg197 animals.
 

Histology

Histopathology in Tg197 mice is characterized by infiltration of inflammatory cells, synovial hyperplasia, articular cartilage destruction and bone erosion symptoms, closely resembling those of human rheumatoid arthritis.

  

Figure 2: Representative histology images of A: wild type and B: Tg197 animals at 10 weeks of age depicting the symptoms of Infiltration of inflammatory cells, Synovial hyperplasia, Articular cartilage destruction and Bone erosions evident as Tg197 arthritic pathology.

Preclinical Efficacy evaluation

Study design

Preclinical drug efficacy can be evaluated either in a:
> prophylactic regimen starting at 3 weeks of age upon disease initiation  and lasting for 7 weeks up to the 10th week of age of the animals. Ideal for the evaluation of therapeutics in peventing the development of disease symptoms.

> therapeutic regimen starting at 6 weeks of age when the disease is fully established and lasting for 6 weeks up to the 12th week of age of the animals. Ideal for the evaluation of therapeutics in reversing disease symptoms.


Figure 3: Tg197 animals can be treated using either a prophylactic or a therapeutic regimen.


Read-out parameters

  • In vivo body weight measurements for the whole duration of the study
  • In vivo evaluation of ankle and paw  joint swelling for the whole duration of the study
  • In vivo evaluation of the progression of arthritis as depicted in the general well being of the animals & the development of cachexia
  • Histopathological  evaluation of the arthritis pathology in ankle joints

       

Figure 4: Representative graphs of the progression of the in vivo arthritic score in Tg197 animals (left panel) and the histopathological arthritic score (right panel) observed at 10 weeks of age. Prophylactic treatment with commercially available anti-hTNF therapeutics prevents the development of disease symptoms.

 

     

Figure 5: Representative graphs of the progression of the in vivo arthritic score in Tg197 animals (left panel) and the histopathological arthritic score (right panel) observed at 12 weeks of age. Therapeutic treatment with commercially available anti-hTNF therapeutics reverses the disease symptoms.
Bibliography
1.  Keffer J., Probert L., Cazlaris H., Georgopoulos S., Kaslaris E., Kioussis D., Kollias G., 1991, "Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis", EMBO J., 10, 4025-4031. (view article).
The article describes the generation and phenotypic characterization of Tg197 model of arthritis.
 
2.  A document showing how Centocor used Tg211, Tg197 and Tg5453 to test Infliximab (view document).

3. A published abstract by Abgenix Biopharma using Tg197 and Tg5453 for testing their antibodies (view abstract).
The article describes the generation and phenotype of the TgK21 mice, a model of multiple sclerosis caused by human TNF.

4. Shealy DJ, Wooley PH, Emmell E, Volk A, Rosenberg A, Treacy G, Wagner CL, Mayton L, Griswold DE, Song XY. 2002, “Anti-TNF-alpha antibody allows healing of joint damage in polyarthritic transgenic mice”. Arthritis Res. 4(5):R7. (view article).
 
5. Brenner D, Blaser H, Mak TW, 2015, "Regulation of tumour necrosis factor signalling: live or let die". Nat. Rev. Immunol., May 26;15(6):362-74. doi: 10.1038/nri3834. (view article).
A recent review that highlights the instrumental role of the Tg197 model of arthritis in providing the proof of concept for the anti-TNF therapy for the efficient treatment of arthritis.