Collagen Induced Arthritis in Mice (Mouse CIA)

Mouse collagen induced arthritis (CIA) is an experimental model of polyarthritis which has been widely used for preclinical testing of numerous anti-arthritic agents which are either under preclinical or clinical investigation or are currently used as therapeutics in this disease..

Induction:

While mice (DBA/1lacJ, 1J or B10Rlll) reliably develop polyarthritis when immunized against bovine type II collagen using a variety of methodologies, we generally recommend immunizing DBA/1 mice on study day 0 and 21 (150 µL of bovine Type II collagen in Freund’s complete adjuvant) without concurrent boosting with endotoxin or recombinant IL-11,2.

Disease Progression/Parameters:

Generally, mice show signs of disease between days 26 to 35 and the disease that occurs is usually not symmetrical and any combination of paws/joints may be affected. Lesions in affected joints resemble those occurring in rat collagen arthritis1.

Dosing Paradigms:

  • Developing (Prophylactic) – Begin dosing on study day 0 and continue until necropsy on day 35.
  • Semi-Established (Prophylactic) – Begin dosing on study day 18 and continue until necropsy on day 35.
  • Established (Therapeutic) – Begin dosing after an animal has a score of at least 1 in one paw (typically study days 26 and 27) and continue for either 10 or 13 days of dosing with necropsy on arthritis day 11 or 14.

Clinical Assessment:

Since caliper measurement of small mouse ankles is challenging, subjective clinical scoring systems are often used in conjunction with histologic scoring methods. Using the method listed below, clinical scores are given from days 18 to 35 in prophylactic dosing and from the first day of enrollment until necropsy in therapeutic dosing.

0 = Normal.

1 = One hind or fore paw joint affected or minimal diffuse erythema and swelling.

2 = Two hind or fore paw joints affected or mild diffuse erythema and swelling.

3 = Three hind or fore paw joints affected or moderate diffuse erythema and swelling.

4 = Four hind or fore paw joints affected or marked diffuse erythema and swelling.

5 = Entire paw affected, severe diffuse erythema and severe swelling, unable to flex digits.

Histopathological Assessment for Mouse CIA joints:

Fore paws, hind paws/ankles, and knees are given scores of 0 through 5 for inflammation, pannus formation, cartilage damage and bone resorption according to these methods.

Sample Data from Mouse CIA model (Click on Image to Enlarge):

Notes:

The Mouse CIA model has been particularly useful in evaluating the effects of clinically used biologic agents such as Interleukin-1 receptor antagonist (IL-1ra) and the soluble TNF receptors 3-7.

Optional Endpoints:

  • PK blood collections
  • Anti-Type II Collagen Antibody ELISA
  • Knee Lavage collection

References:

  1. Bendele AM. Animal Models of Rheumatoid Arthritis. J Musculoskel Interact 2001; 4: 377– 385.
  2. Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen: an experimental model of arthritis. J Exp Med 1977; 146(3): 857–868.
  3. Wooley PH, Whalen JD, Chapman DL, Berger AE, Richard KA, Aspar DG, Staite ND. The effect of an interleukin-1 receptor antagonist protein on type II collagen-induced arthritis and antigen-induced arthritis in mice. Arthritis Rheum 1993; 36:1305-1314.
  4. Bakker, AC, Joosten LAB, Arntz OJ, Helsen MA, Bendele AM, van de Loo AJ, van den Berg WB. Gene therapy of murine collagen-induced arthritis: local expression of the human interleukin-1 receptor antagonist protein prevents onset. Arthritis Rheum 1997; 40:893-900.
  5. Joosten LAB, Helsen MMA, van de Loo FAJ, van den Berg WB. Amelioration of established type II collagen- induced arthritis (CIA) with anti-IL-1. Agents Actions 1994; 41:C174-C176.
  6. Joosten LAB, Helsen MMA, van de Loo FAJ, van den Berg WB. Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. Arthritis Rheum 1996; 39:797-809.
  7. Geiger T, Towbin H, Cosenti-vargas A, Zingel O, Arnold J, Rordorf C, Glatt M, Vosbeck K. Neutralization of interleukin-1 μ activity in vivo with a monoclonal antibody alleviates collagen-induced arthritis in DBA/1 mice and prevents the associated acute phase response. Clin Exp Rheumatol 1993; 11:515-522.

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