Model of arthritis

Study of Chemokines in Different Experimental Models of Arthritis... 

Different approaches have been used to probe the role of chemokines and their receptors in experimental models of arthritis for instance, peptide antagonists or immunization of the host to promote the generation of endogenous neutralizing Abs via the use of chemokine plasmid DNA vaccination (Table 4 and Ref. 50), injection of neutralizing antibodies (Table 5), or mice that lack specific chemokine or chemokine receptors (Table 6). 

In addition to CIA, there are several other models of arthritis that have also provided evidence for an important role of the chemokine system. Next, we will review some of the data available regarding the contribution of chemokines to disease pathogenesis in specific model systems beyond mere description of any given factor in the joints. 

Target Model of arthritis Species Peptide/DNA Clinical effect Potential mechanism/comments Ref. 

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

Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor a predictive genetic model of arthritis. EMBO J I99l 10(13) 4025 t031. 

Podolin PL, Bolognese BJ, Foley JJ, et al. A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol 2002 169(ll) 6435-6444. 

Nitric oxide has a role in both acute and chronic inflammation. NOS-3 is involved in the vasodilation associated with acute inflammation. In experimental models of acute inflammation, inhibitors of NOS-3 have a dose-dependent protective effect, suggesting that nitric oxide promotes edema and vascular permeability. Nitric oxide has a detrimental effect in chronic models of arthritis dietary L-arginine supplementation exacerbates arthritis whereas protection is seen with NOS-2 inhibitors. Psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of nitric oxide and NOS-2. Synovial fluid from patients with arthritis contains increased oxidation products of nitric oxide, particularly peroxynitrite. 

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). 

The above observations clearly indicate that IL-4 is an important neutrophil activator in vitro. Recently, one study was conducted in order to assess the capacity of IL-4 and IL-IO to block neutrophil activation in an ex vivo human model system, and to confirm their effect on neutrophil function in an animal model of arthritis [75]. In the rat adjuvant arthritis model, treatment with systemic murine IL-4 (mIL-4 and mIL-10) was found to be effective against even the most severely diseased [75]. IL-4 (and IL-10) was effective in lowering the absolute neutrophil cell number recovered and the neutrophil activation state in the joint synovia. Both cytokines reduced the phagocytic activation of human neutrophils in response to proinflammatory cytokines. Collectively, the results demonstrate that IL-4 (and IL-10) can exert powerful regulatory effects on neutrophil function that translate into a therapeutic response in a disease model of arthritis. The authors concluded that treatment with IL-4 (or IL-10) alone or in combination might therefore be very usefiil in the management of patients with rheumatoid arthritis [75]. 

Bober LA, Rojas-Triana A, Jackson JV, Leach MW, Manfra D, Narula SK, Grace MJ Regulatory effects of interleuldn-4 and interleukin-10 on human neutrophil function ex vivo and on neutrophil influx in a rat model of arthritis. Arthritis Rheum 2000 43 2660-2667. 

Chemokines regulate the migration of cells in vivo and dysregulated expression of chemokines and their receptors are implicated in autoimmune and inflammatory diseases. Inflammatory arthritides, such as rheumatoid arthritis (RA), are characterized by the recruitment of inflammatory cells into joints. The K/BxN serum transfer mouse model of inflammatory arthritis shares many similar features with RA. In this autoantibody-induced model of arthritis, neutrophils are the critical immune cells necessary for the development of joint inflammation and damage. In this review, we describe the use of several methods to study the role of chemoattractant receptors, including chemokine receptors, on the recruitment of neutrophils into the joint in the K/BxN model of inflammatory arthritis. This includes both traditional methods, such as flow cytometry, immunohistochemistry, and enzyme assays, as well as multiphoton in vivo microscopy that we have adapted to study the role of immune cell trafficking in and around the joint in live mice. 

Yudoh K, Karasawa R, Masuko K, Kato T. Water-soluble fullerene (C60) inhibits the development of arthritis in the rat model of arthritis, hit J Nanomed 2009 4 217-25. 

These data demonstrate the involvement of chemokines and their receptors in inflammatory joint disease. Further information on the role of chemokines and chemokine receptors should come from the use of transgenic or knockout mice in animal models of arthritis. It is clear that blocking the interactions between chemokines and their receptors using antichemokine, antichemokine receptor monoclonal antibodies, or chemokine receptor antagonists may prove to be of therapeutic value in the control inflammatory diseases such as rheumatoid arthritis. 

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