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Target effector role of vascular endothelium in the inflammatory response: insights from the clinical trial of anti-TNF alpha antibody in rheumatoid arthritis.
  1. E Paleolog
  1. Kennedy Institute of Rheumatology, London, UK. e.paleolog@cxwms.ac.uk

    Abstract

    Rheumatoid arthritis (RA) is characterised by chronic joint inflammation and infiltration by cells from the blood, especially activated T cells and macrophages, together with formation of new blood vessels. The overgrowth of the synovial lesion results eventually in destruction of cartilage and bone. Cytokines play a major role in RA, both in systemic inflammatory processes, such as induction of acute phase protein synthesis, and in the stimulation of new blood vessel development and recruitment of leucocytes to developing lesions. The focus for the interplay of many cytokines is the endothelium, the lining layer of the vasculature. This is the primary target for circulating mediators, and it controls the traffic of cells and molecules from the bloodstream into underlying tissues. Targeting the action of individual cytokines--for example, using antibody against tumour necrosis factor alpha (TNF alpha), has been shown to be very effective in the treatment of RA. Blockade of TNF alpha activity results in deactivation of the endothelium, manifested as reduced expression of adhesion molecules and chemoattractant cytokines, leading to diminished trafficking of inflammatory cells to synovial joints. In addition anti-TNF alpha decreases circulating levels of the potent angiogenic cytokine VEGF, suggesting that new blood vessel formation, and hence the supply of nutrients to the growing synovial lesion, is also affected. These observations lend further support to the hypothesis that interruption of a component of the cytokine network in RA may modulate disease progression, and point the way towards the development of new therapeutic strategies for the treatment of chronic inflammatory disease states.

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