Arthritis, animal models

P2X7 Antagonists in a rheumatoid arthritis animal model... 

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

In addition to antibodies targeting the CD3 subunit of the TCR complex, antibodies against the a and (3 subunits of the TCR have been tested as therapeutic agents. A benefit for the treatment experimental autoimmune encephalomyelitis or collagen induced arthritis could be shown in animal models [8]. 

Van den Berg WB. Lessons from animal models of arthritis. Curr Rheumatol Rep 2002 4(3) 232—239. 

Anthony DD, Haqqi TM. Collagen-induced arthritis in mice an animal model to study the pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 1999 17(2) 240-244. 

Brahn E. Animal models of rheumatoid arthritis. Clues to etiology and treatment. Clin Orthop 1991(265) 42-53. 

Weekes J et al. Bovine dilated cardiomyopathy proteomic analysis of an animal model of human dilated cardiomyopathy Electrophoresis 1999 20 898-906. Doherty NS et al. Analysis of changes in acute phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two-dimensional gel electrophoresis. Electrophoresis 1998 19 355-363. 

Genetically predisposed animals or induced animal models may also be used to study and predict chemical-induced autoimmunity. In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an autoantigen isolated from the target organ. Examples are adjuvant arthritis (AA), experimental allergic encephalomyelitis (EAE) and experimental uveitis in the Lewis strain rat. Examples of spontaneous models... 

ARRY-438162 was found to be efficacious in a number of animal models of inflammation. For example, in a collagen-induced arthritis model in rats, oral administration of ARRY-438162 at lOmg/kg q.d. significantly inhibited paw swelling which was accompanied by inhibition of cartilage damage in the joint and >80% inhibition of pERK in the tissue from the foot with induced arthritis. 

Finally, NO has significant involvement in both acute and chronic inflammation. In acute inflammation, NO promotes swelling and increased vascular permeability. In animal models of acute inflammation, NOS inhibitors have a dose-dependent protective effect. In models of chronic inflammation (arthritis), NO is detrimental and L-arginine supplementation causes inflammatory exacerbation. At a molecular level, NO stimulates inflammation by activating the cyclooxygenase enzyme. Further supportive data are provided by the observation that fluid drained from the swollen joints of people with arthritis contains peroxynitrate and other oxidation products of NO. 

The nonobese diabetic mouse (NOD), as well as the biobreeding (BB) rats are the two rodent models whose diabetes-related immunopathology is considered to be quite similar to that in humans. Studies in these animal models have revealed that autoreactive T cells that mediate islet 8 cell destruction belong to the Thl subset of T cells (produce IL-2 and IFN-7), whereas regulatory T cells are of the Th2 type (produce IL-4 and IL-10). Because Thl and Th2 cells are mutually inhibitory, there have been many trials using IL-4 and/or IL-10 for the prevention of autoimmune disease, like autoimmune diabetes, rheumatoid arthritis (Evans et al., 1996 Boyle et al., 1999), and inflammatory bowel disease (Rogy et al., 2000). 

Collagen-induced arthritis (CIA) in mice is an animal model for rheumatoid arthritis (RA) and can be induced in DBA/1 and C57BL/6 mice using different protocols. The CIA model can be used to unravel mechanisms involved in the development of arthritis and is frequently used to study the effect of new therapeutics. The development of a CIA model in C57BL/6 mice recently enabled researchers to use knockout mice on this background for arthritis research. 

Kannan, K., Ortmann, R. A. and Kimpel, D. (2005) Animal models of rheumatoid arthritis and their relevance to human disease. Pathophysiology 12, 167-181. 

Hegen, M., Keith, J. C., Jr., Collins, M. and Nickerson-Nutter, C. L. (2008) Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum )A67(11) 1505-1515. 

Young, D. A., Hegen, M., Ma, H. L., Whitters, M. J., Albert, L. M., Lowe, L., et al. (2007) Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 56, 1152-1163. 

Bl. Badger, A. M., Bradbeer, J. N., Votta, B., Lee, J. C., Adams, J. L., and Griswold, D. E., Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J. Pharmacol. Exp. Ther. 279, 1453-1461 (1996). 

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