Chemokine Receptors and Rheumatoid Arthritis

Cure Arthritis Naturally

Cure Arthritis Naturally

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and massive infiltration of leukocytes into the inflamed joints. In RA, a large number of CD4+ memory T-cells infiltrate the inflamed synovium (Kohem, 1996; Morimoto et al., 1988; Morita et al., 1998), where they get activated as they express cytokines and activation makers (Cohen et al., 1995; Dolhain et al., 1996; Grom et al., 1996; MacDonald, 1997; Nanki et al., 2000a,b; Smeets et al., 1998). Inflammatory cytokines [including IL-1, IL-6, IFN-g, and tumor necrosis factor (TNF)-a] and activation markers are known to play central roles in the pathogenesis of RA (Nanki et al., 2000a). Although the development of biological drugs targeting these cytokines has produced promising results in the clinical therapy of RA patients, the design of other drugs that are independent of cytokine's function is needed for the improvement of RA chemotherapy. Previously, Nanki et al. reported that the memory T-cells express a chemokine receptor CXCR4 at a high level and that the concentration of SDF-1 a, an endogenous ligand of CXCR4, is extremely high in the synovium of RA patients. It is also found that SDF-1 a stimulates the migration of memory T-cells and inhibits T-cell apoptosis, suggesting that the SDF-1 a-CXCR4 interaction plays an important role in the accumulation of T-cells in the RA synovium (Nanki et al., 2000b). Since SDF-1a (Nagasawa and Kishimoto, 1994; Tashiro et al., 1993) is independent of the other inflammatory cytokines in terms of its expression and function, the development of inhibitors that blocks the SDF-1 a-CXCR4 interaction might produce promising leads for RA therapy.

Several recent publications support the involvement of SDF-1 a-CXCR4 interaction in memory T-cell migration in the inflamed RA synovium. For instance, several CXCR4 antagonists, including T22 (an 18-mer peptide) (Murakami et al., 1997), T140 (a 14-mer) (Tamamura et al., 1998), and FC131 (a cyclic pentapeptide) (Fujii et al., 2003), which have inhibitory activities against the entry of T-cell line-tropic (X4-) HIV-1 into the target cells (Murakami etal., 1997,1999; Xu et al., 1999), are known to have anti-RA activities. De Clercq's group also reported that another

CXCR4 antagonist, AMD3100, has both anti-HIV-1 and anti-RA activities (Hendrix et al., 2000; Schols et al., 1997). AMD3100is a bicyclam derivative first described for its potent activity against HIV-1 infection (De Clercq et al., 1992) and is currently under investigation for clinical applicability in AIDS patients (De Clercq et al., 1994). However, the clinical applications of AMD3100 are limited by the fact that this compound is rapidly cleared from circulation, and that the treatment schedule in mice requires the use of osmotic minipumps (Datema et al., 1996).

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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