Rheumatoid Arthritis: Bondeson J

Feldmann M, Andreakos E, Smith C, Bondeson J, Yoshimura S, Kiriakidis S, Monaco C, Gasparini C, Sacre S, Lundberg A, Paleolog E, Horwood NJ, Brennan FM, Foxwell BM. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Charing Cross Hospital Campus, Arthritis Research Campaign Building, 1 Aspenlea Road, London W6 8LH, UK. · Ann Rheum Dis. · Pubmed #12379614 links to  free full text

Abstract: There is increasing evidence that NF-kappaB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-kappaB might be therapeutically beneficial, it raises clear questions regarding the balance between efficacy and safety. In this brief review we discuss the effects of NF-kappaB blockade in rheumatoid arthritis, inflammation and immunity, and consider possible therapeutic targets within the NF-kappaB family.

Feldmann M, Maini RN, Bondeson J, Taylor P, Foxwell BM, Brennan FM. · Kennedy Institute of Rheumatology, Hammersmith, London, UK. · Adv Exp Med Biol. · Pubmed #11505970 No free full text.

Abstract: As we enter the 2000's it is clear that cytokine blockade is an effective therapeutic strategy for rheumatoid arthritis. In this brief review, we will review the rationale for anti TNFalpha therapy, the current status of therapy and focus on the regulation of TNFalpha production in rheumatoid synovium. New approaches to studying TNF regulation in RA and of elucidating the controversial role of T cells in this complex disease will be described.

Bondeson J, Maini RN. · Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, UK. · Int J Clin Pract. · Pubmed #11351775 No free full text.

Abstract: Therapeutic strategies that aim to neutralise the important pro-inflammatory cytokine tumour necrosis factor alpha (TNF alpha) have gained considerable prominence in the therapy of chronic inflammatory diseases, notably rheumatoid arthritis and Crohn's disease. This drug focus review will concentrate on the antitumour necrosis factor antibody infliximab (Remicade), which has been approved for the treatment of rheumatoid arthritis and Crohn's disease in both the US and Europe. In addition, infliximab is under investigation for several other indications, mainly inflammatory rheumatic diseases. Clinical trials have been persuasive that infliximab is both safe and effective, and it has been proven to be far superior to the conventional drug therapy in both rheumatoid arthritis and Crohn's disease. Remarkably, infliximab in combination with methotrexate controls both the inflammatory joint symptoms and the progression of joint damage, which renders it a very attractive therapeutic option in moderate to severe, therapy-resistant rheumatoid arthritis.

Foxwell BM, Bondeson J, Brennan F, Feldmann M. · Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, Hammersmith, London, UK. · Ann Rheum Dis. · Pubmed #11053090 links to  free full text

Abstract: The success of anti-tumour necrosis factor (TNF) treatment, either using antibodies or soluble receptors, has defined TNF as a major factor of the inflammatory response in rheumatoid arthritis (RA). As a result of this success, much attention has been devoted to understanding the molecular mechanisms by which TNF expression and activity is elicited and controlled. By understanding these pathways, it is hoped that key elements of the molecular pathology associated with RA will be uncovered and, as a result, new targets for therapeutic intervention will be identified. However, studying the cell and molecular biology of model systems for RA, such as primary human macrophages, or tissue from rheumatoid joints may present technical problems. In an attempt to overcome this, we have investigated the use of adenovirus as a means of delivering transgenes by which different intracellular pathways can be modulated and examined. Our data show that adenovirus can be successfully used to efficiently deliver transgenes to primary human macrophages and RA joint tissue. Using a virus encoding IkappaBalpha, the natural inhibitor of NFkappaB, we show that the requirement for the transcription factor is not universal, but is dependent on the nature of the stimulus. Furthermore, while NFkappaB is of importance for the expression of TNF and other pro-inflammatory cytokines (for example, interleukin 6) and the destructive matrix metalloproteinases, this factor is not required for the expression of anti-inflammatory cytokines interleukin 10 and interleukin 1 receptor antagonist.

Feldmann M, Bondeson J, Brennan FM, Foxwell BM, Maini RN. · Kennedy Institute of Rheumatology, 1 Aspenlea Road Hammersmith London W6 8LH. · Ann Rheum Dis. · Pubmed #10577970 links to  free full text

Abstract: Progress in understanding mechanisms of disease are necessary to usher in major changes in treatment. A new era in rheumatoid arthritis (RA) and related chronic autoimmune/inflammatory diseases is now beginning, with a variety of anti-TNFalpha treatments licensed for use in both RA and Crohn's disease. The rationale for this new treatment lies in an understanding that cytokines are critical, rate limiting molecules lying at the heart of the chronic autoimmune/inflammatory disease process. This understanding was developed from the critical evaluation of a hypothesis that was proposed linking cytokines, antigen presentation and autoimmunity in 1983. Detailed analysis focusing on the major site of the disease, the rheumatoid synovium was essential to developing indications that blockade of TNFalpha might be efficacious. This clue was validated using anti-TNFalpha treatment of an animal model of RA, murine collagen induced arthritis, and by immunohistochemical demonstration of upregulated TNF and TNF-R expression in the synovium. With this three pronged rationale, the authors were able to convince Centocor, Inc, which had developed a chimaeric anti-TNFalpha antibody for use in sepsis, to work with them to test the concept that TNFalpha blockade would be beneficial in RA. With the success of that first trial, other companies have subsequently tested their anti-TNF strategies successfully. Current interests extend to understanding the processes that regulate TNF production in the rheumatoid joint. Progress in this area is discussed, using adenoviruses to infect normal macrophages and rheumatoid synovium.

Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE. · Department of Rheumatology, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. · Arthritis Res Ther. · Pubmed #17177994 links to  free full text

Abstract: There is an increasing body of evidence that synovitis plays a role in the progression of osteoarthritis and that overproduction of cytokines and growth factors from the inflamed synovium can influence the production of degradative enzymes and the destruction of cartilage. In this study, we investigate the role of synovial macrophages and their main proinflammatory cytokines, interleukin (IL)-1 and tumour necrosis factor-alpha (TNF-alpha), in driving osteoarthritis synovitis and influencing the production of other pro- and anti-inflammatory cytokines, production of matrix metalloproteinases, and expression of aggrecanases in the osteoarthritis synovium. We established a model of cultures of synovial cells from digested osteoarthritis synovium derived from patients undergoing knee or hip arthroplasties. By means of anti-CD14-conjugated magnetic beads, specific depletion of osteoarthritis synovial macrophages from these cultures could be achieved. The CD14+-depleted cultures no longer produced significant amounts of macrophage-derived cytokines like IL-1 and TNF-alpha. Interestingly, there was also significant downregulation of several cytokines, such as IL-6 and IL-8 (p < 0.001) and matrix metalloproteinases 1 and 3 (p < 0.01), produced chiefly by synovial fibroblasts. To investigate the mechanisms involved, we went on to use specific downregulation of IL-1 and/or TNF-alpha in these osteoarthritis cultures of synovial cells. The results indicated that neutralisation of both IL-1 and TNF-alpha was needed to achieve a degree of cytokine (IL-6, IL-8, and monocyte chemoattractant protein-1) and matrix metalloproteinase (1, 3, 9, and 13) inhibition, as assessed by enzyme-linked immunosorbent assay and by reverse transcription-polymerase chain reaction (RT-PCR), similar to that observed in CD14+-depleted cultures. Another interesting observation was that in these osteoarthritis cultures of synovial cells, IL-1beta production was independent of TNF-alpha, in contrast to the situation in rheumatoid arthritis. Using RT-PCR, we also demonstrated that whereas the ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4) aggrecanase was driven mainly by TNF-alpha, ADAMTS5 was not affected by neutralisation of IL-1 and/or TNF-alpha. These results suggest that, in the osteoarthritis synovium, both inflammatory and destructive responses are dependent largely on macrophages and that these effects are cytokine-driven through a combination of IL-1 and TNF-alpha.

Amos N, Lauder S, Evans A, Feldmann M, Bondeson J. · Department of Rheumatology, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. · Rheumatology (Oxford). · Pubmed #16571608 links to  free full text

Abstract: OBJECTIVES: Despite recent major advances in the understanding of the pathogenesis of rheumatoid arthritis, with tumour necrosis factor-alpha (TNFalpha) established as a major therapeutic target, comparatively little is known about the mediators involved in the destructive and inflammatory pathways in osteoarthritis (OA). Recently, it has become appreciated that an inflammatory synovitis contributes not only to the signs and symptoms of osteoarthritis, but also to disease progression. Here, we use high-efficiency adenoviral gene transfer to investigate the role of the transcription factor nuclear factor-kappaB (NFkappaB) in regulating inflammatory and destructive mediators in the late stage OA synovium. METHODS: Infection with reporter adenoviruses transferring the beta-galactosidase or green fluorescent protein genes verified that OA synovial cells could be infected (>95%). Adenovirus transferring the inhibitory subunit IkappaBalpha inhibited NFkappaB. The production of a whole array of pro- and anti-inflammatory cytokines and mediators, and several matrix metalloproteinases and their main inhibitor, was measured by enzyme-linked immunosorbent assay. RESULTS: The spontaneous production of macrophage-produced pro-inflammatory cytokines varied: TNFalpha was modestly inhibited by IkappaBalpha overexpression, but interleukin (IL)-1 was unaffected. Both IL-6 and IL-8 were potently inhibited, as were granulocyte-macrophage colony stimulating factor and oncostatin M. Anti-inflammatory mediators like IL-10, the IL-1 receptor antagonist and the p55 soluble TNF receptor were unaffected. Matrix metalloproteinases 1, 3, 9 and 13 were potently inhibited by IkappaBalpha overexpression, but not their main inhibitor tissue inhibitor of metalloproteinase-1. CONCLUSIONS: The OA synovium is a highly inflammatory environment, with spontaneous production of many cytokines and matrix metalloproteinases. Inhibition of NFkappaB may have a beneficial effect on the balance between pro-inflammatory cytokines and anti-inflammatory mediators, and between destructive metalloproteinases and their main inhibitor.

Feldmann M, Brennan F, Bondeson J, Paleolog E, Foxwell B, Maini R. · Kennedy Institute of Rheumatology, London, UK. · Transplant Proc. · Pubmed #11377461 No free full text.

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Bondeson J, Brennan F, Foxwell B, Feldmann M. · Kennedy Institute of Rheumatology, London, UK. · J Rheumatol. · Pubmed #10990217 No free full text.

Abstract: OBJECTIVE: To determine whether, in human fibroblasts and chondrosarcoma cells, the regulation of interleukins (IL)-6, 8, and 11 and matrix metalloproteinases (MMP)-1, 3, and 13, and their tissue inhibitor TIMP-1, depends on the transcription factor nuclear factor-kappaB (NF-kappaB). METHODS: Fibroblasts and chondrosarcoma cells were effectively infected with an adenovirus encoding human IkappaBalpha, and inhibition of NF-kappaB function was observed. The induction of MMP and IL-6, 8, and 11 by various stimuli was assessed by ELISA. RESULTS: The induction of IL-6 and IL-8 clearly depended on NF-kappaB in both fibroblasts and chondrosarcoma cells, irrespective of stimulus, but IkappaBalpha overexpression had little effect on IL-11. MMP-1, -3, and -13 were also inhibited, but TIMP-1 was unaffected. CONCLUSION: NF-kappaB appears to play an important and selective role in MMP induction in human fibroblasts and chondrosarcoma cells. This suggests there are NF-kappaB dependent mechanisms of cartilage destruction in rheumatoid arthritis, and supports the concept that there are similarities in the regulation of inflammatory and destructive pathways in that disease.

Bondeson J, Foxwell B, Brennan F, Feldmann M. · Kennedy Institute of Rheumatology, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom. · Proc Natl Acad Sci U S A. · Pubmed #10318942 links to  free full text

Abstract: The role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself.

Bondeson J, Browne KA, Brennan FM, Foxwell BM, Feldmann M. · Kennedy Institute of Rheumatology, Hammersmith, London, United Kingdom. · J Immunol. · Pubmed #10072544 links to  free full text

Abstract: Macrophages are the major cytokine producers in chronic inflammatory diseases, but the biochemical pathways regulating cytokine production are poorly understood. This is because genetic tools to dissect signaling pathways cannot be used in macrophages because of difficulties in transfection. We have developed an adenoviral technique to achieve high efficiency gene delivery into macrophages and recently showed that spontaneous TNF-alpha production in rheumatoid arthritis joint cells, chiefly from macrophages, is 75% blocked by adenoviral transfer of IkappaBalpha. In this report we use the same adenovirus to investigate whether the production of a number of proinflammatory cytokines (e.g., TNF-alpha, IL-1beta, IL-6, and IL-8) from human macrophages depends on NF-kappaB. While the cytokine response to certain inducers, such as LPS, PMA, and UV light, is blocked by overexpression of IkappaBalpha, the response to zymosan is not. In contrast, anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist) induced by LPS are only marginally inhibited by IkappaBalpha excess. These studies demonstrate several new points about macrophage cytokine production. First, there is heterogeneity of mechanisms regulating both the proinflammatory and anti-inflammatory cytokines within populations of a single cell type. In addition, the results confirm the utility of the adenoviral technique for functional analysis of cytokine induction. The results also confirm that there are autocrine and paracrine interactions regulating cytokine synthesis within a single cell type. The selectivity of NF-kappaB blockade for proinflammatory but not anti-inflammatory mediators indicates that in macrophages, NF-kappaB may be a good target for the treatment of chronic inflammatory diseases.