Rheumatoid Arthritis

Apart from arthrosis, rheumatoid arthritis is the most prevalent (approximately 1% in Caucasians) and severe chronic inflammatory disease of the joints, with a particularly high socioeconomic impact. It is thought to be an immune-mediated disease that promotes inflammation and progressive destruction of the joints. Besides the pro-inflammatory cytokines TNFa, IL-1 p and IL-6, which mainly derive from macrophages, a dominant type 1 Th cell response is associated with the disease that is characterized by an imbalance of IFN-g over IL-4.30 While TNFa and IL-1p may signal via the transcription factor NF-kB, IL-6 and in particular IFN-g exert their pro-inflammatory effects through activation of members of the Stat family of transcription factors, namely Stat-1. Stat-1 in turn upregulates expression, for example of the co-stimulatory molecule CD40, either by direct binding to the interferon g-activated sequence (GAS) element in the CD40 promoter or by inducing the de novo synthesis of the transcription factor IFN regulatory factor-1 (IRF-1).35,36 Interesting therapeutic targets for a decoy ODN approach, therefore, are proinflammatory transcription factors, such as NF-kB or Stat-1. Decoy ODNs directed against these two transcription factors have been tested in two different animal models, collagen-induced arthritis in the rat and antigen-induced arthritis in mice. Both decoy ODNs were administered by intra-articular injection. While the NF-kB decoy ODN was encapsulated into HVJ-liposomes, the Stat-1 decoy ODN was administered as naked DNA prior to the ultimate challenge with the antigen. Single treatment with the Stat-1 decoy ODN exerted a profound and dose-dependent (0.05-10 nmol, near-maximum effect at 0.25 nmol) inhibitory effect not only on joint swelling and the histopathological signs of both acute and chronic arthritis, but also on delayed-type hypersensitivity and cytokine release into the synovia. Moreover, CD40 mRNA expression in stimulated macrophages was downregulated, and these effects of the decoy ODN were mimicked by intra-articular injection of a monoclonal antibody neutralizing the CD40 ligand CD154.30 It was concluded, therefore, that the beneficial effect of the Stat-1 decoy ODN in this model was mediated in part by affecting CD40 signalling in macrophages and/or other antigen-presenting cells. In the collagen-induced arthritis model, intra-arterial injection of the liposomal NF-kB decoy ODN formulation also afforded a marked suppression of joint destruction as well as cytokine release into the synovia.37 When translating these findings into the situation in human rheumatoid arthritis that does not normally affect a single joint only, however, a note of caution may be appropriate with respect to the route of administration taken in the aforementioned studies. Here, a systemic delivery method is a must. Moreover, with respect to the relevance of these two models it is stressed that the cartilage destruction seen in the murine antigen-induced arthritis model more closely resembles the human disease. Recently, another decoy ODN approach targeted at the transcription factor E2F has been shown to exert a protective effect in immunodeficient severe combined immune deficiency (SCID) mice that were transplanted with human cartilage and rheumatoid arthritis tissue, probably through inhibition of synovial cell proliferation.38

As mentioned before, NO is a potent anti-inflammatory mediator and the primarily anti-inflammatory cytokine IL-10 is capable of upregulating eNOS expression in human endothelial cells through activation of the transcription factor Stat-3.39 Moreover, the resulting increase in NO production blocks the CD40-mediated expression of the pro-inflammatory cytokine IL-12 in the endothelial cells. However, in endothelial cells derived from individuals that are homozygous for the T-786C SNP of the eNOS gene, IL-10 fails to upre-gulate eNOS expression.15 In addition, the affected individuals had a significantly increased risk to develop rheumatoid arthritis. As with the SNP in the context of CHD, pre-incubation of C/C genotype endothelial cells with a decoy ODN directed against the C-type but not the T-type NO synthase gene promoter also restored the responsiveness of the defective gene to IL-10. The same effect could be achieved with decoy ODNs as small as 10 base pairs, provided these were directed against the C-type promoter around position -786. The molecular basis of this additional deblocking effect of the decoy ODNs is that Stat-3, the intracellular mediator of the effect of IL-10, exerts its effect on eNOS expression by binding to a generic Stat motif approximately 60 base pairs upstream of the mutation. Again, it appears that the putative inhibitory DNA-binding protein that binds with high affinity to the mutated sequence (see above) sterically hinders Stat-3 from inducing expression of the eNOS gene. As a result, the NO-synthesizing capacity of the endothelial cells in response to IL-10 is weakened, leading to an increased risk of inflammation in the joints of individuals homozygous for the T-786C SNP of the eNOS gene. As with CHD, this context provides another opportunity for employing decoy ODNs as a novel approach towards personalized medicine. Moreover, these findings point towards a common pathogenetic basis of CHD and rheumatoid arthritis in which the eNOS gene has an important modifying role. Clinically, the increased risk of patients with rheumatoid arthritis to contract CHD and vice versa is well known.40,41

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