Model Description

In the Collagen Antibody Induced Arthritis (CAIA) model, arthritis is stimulated through the administration of a cocktail of monoclonal antibodies that are directed to conserved auto-antigenic epitopes of collagen type II, followed by endotoxin challenge. 3-4 days after the initial disease induction step, the Tg1278TNFKo/CAIA model starts developing pathology characterized by severe inflammation of all 4 mouse limbs. The incidence is 90-100% and symptoms persist up to several weeks after the induction. 

Preclinical Efficacy evaluation

Study design

A Tg1278TNFKo/CAIA study is normally completed  in 2 weeks time. A standard protocol involves a therapeutic regimen with administration of therapeutics starting after the LPS boost, when pathology has already started developing. 

Read-out parameters

• In-vivo arthritis score on daily basis, involving evaluation of the front and hind paw swelling
• Body weight measured and recorded tri-weekly
• Serum/plasma processed from blood obtained by cardiac puncture at the end of the study
• Histopathological evaluation of front and hind paw pathology after the end of the study (day 13)

Histopathology in the Tg1278TNFKo/CAIA model has characteristics of the human arthritis pathology including infiltration of inflammatory cells (H&E staining), cartilage destruction (toluidine blue staining), bone erosion (TRAPS staining) etc. Therapeutic regimen with high dose (10 mg/kg) of Remicade significantly improves all signs of pathology. 

Arthritis scoring in Tg1278TNFKo mice after CAIA induction and over a period of 26 days. Therapeutic regimen with low (1 mg/kg) and high (10 mg/kg) doses of Remicade (left) or with high doses of Remicade (10 mg/kg), Humira (10 mg/kg) and Enbrel (30 mg/kg) significantly ameliorates arthritis 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 of Tg1278 transgenic.

2. Pasparakis M., Alexopoulou L., Episkopou V., Kollias G., 1996, "Immune and Inflammatory Responses in TNFα-deficient Mice: A Critical Requirement for TNFα in the Formation of Primary B Cell Follicles, Follicular Dendritic Cell Networks and Germinal Centers, and in the Maturation of the Humoral Immune Response", JEM, 184(4), 1397-411 (view article).
This article shows how TNF expression from Tg1278 transgene, allows the restoration of TNF function in TNF ko mice.

3. Moore A, Allden S, Bourne T, Denis MC, Kranidioti K, Okoye R, Sotsios Y, Stencel Z, Vugler A, Watt G, et al., 2014. "Collagen II antibody-induced arthritis in Tg1278TNFko mice: optimization of a novel model to assess treatments targeting human TNFα in rheumatoid arthritis".  J Transl Med., 12(1):285 (view article).
The paper demonstrates that Tg1278TNFko mice is a well-suited animal model for testing the next generation of therapeutics targeting human TNFα in rheumatoid arthritis.