Model description

Arthritis in TNFΔARE mice is characterized by ankle swelling, hind limb distortion, impaired movement and progressive weight loss. Symptoms start to develop at 3 weeks of age and disease has fully developed by 10 weeks of age.

Intestinal inflammation in TNFΔARE mice is clinically indicated by weight loss and the disease fully develops by 8 weeks of age.
 

Histology

Intestinal inflammation: The terminal ileum of the TNFΔARE mice shows profound inflammatory changes consistent with Crohn's disease-like phenotype. Villi are blunted and broadened and there is extended mucosal and submucosal infiltration of chronic as well as acute inflammatory cells.

  
Figure 1: Representative images depicting intestinal inflammation in TNFΔARE mice. Treatment with Enbrel ameliorates disease symptoms.

Arthritis: Joints of TNFΔARE mice display severe pathological features of chronic symmetrical inflammatory polyarthritis, including hyperplasia of the synovial membrane, presence of inflammatory infiltrate, bone erosion and articular cartilage destruction.

   
Figure 2: Representative images depicting arthritis pathology in TNFΔARE mice. Treatment with Enbrel ameliorates disease symptoms.

Preclinical Efficacy evaluation

Study design

Preclinical drug efficacy is evaluated in a prophylactic regimen starting at 4 weeks of age upon disease initiation and lasts for 8 weeks. 

Read-out parameters

  • body weight measurements
  • grip strenght measurements (in vivo arthritis measurements)
  • histolopathological evaluation of the joints (arthritis)
  • histopathological evaluation of intestine (IBD)


Figure 3: Representative graphs depicting the progressive body weight gain (left panel) and grip strenght (right panel) in TNFΔARE animals. Treatment with anti-TNF biologics reverses the disease symptoms.


Figure 4: Representative graphs depicting histopathological scores of arthritis & IBD in TNFΔARE animals. Treatment with anti-TNF biologics reduces signs of both pathologies.

Bibliography

1. Kontoyiannis D., Pasparakis M., Pizarro T. T., Cominelli F., Kollias G., 1999, "Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies", Immunity, 10, 387-398 (view article). 
The article describes the generation and characterization of the TNFΔARE line, a unique model that develops both arthritis and Crohn’s disease. This model has been used by Chemocentryx for testing a CCR9 inhibitor for Crohn's disease.

2. Kontoyiannis D., Boulougouris G., Manoloukos M., Armaka M., Apostolaki M., Pizarro T., Kotlyarov A., Forster I., Flavell R., Gaestel M., Tsichlis P., Cominelli F., Kollias G.,2002, "Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease", JEM, 196, 1563-74. (view article)