Search

Abstract: Proinflammatory cytokines such as TNFα and IL-1β are produced in lesional skin of chronic plaque psoriasis patients, and at other sites of chronic inflammation such as arthritic joints. They play vital roles in maintaining inflammation. It has recently been suggested that activated T cell contact-mediated monocyte activation, leading to the production of proinflammatory cytokines, contributes to the pathogenesis of psoriasis and other chronic inflammatory diseases such as psoriatic arthritis and rheumatoid arthritis. Using a T cell membrane–monocyte contact bioassay, we have identified small molecule antagonists that differentially block anti-CD3/anti-CD28 activated T cell-mediated, but not LPS-stimulated, TNFα production from monocytes. We selected several kinase inhibitors from the Berlex/Schering kinase library and tested the effect of these compounds in blocking TNFα production in the T cell membrane–monocyte contact bioassay. We have demonstrated that one compound BLX-1, from a p38 MAP kinase inhibitor project, inhibited T cell-mediated TNFα production from monocytes by about 80%, without any effect on TNFα production from LPS-stimulated monocytes. Other BLX-1 analogs showed 32–83% inhibition of TNFα production with LPS stimulation as compared to almost 100% inhibition of T cell-mediated TNFα production. In contrast, PKC inhibitors BLX-5, Go6983, and Ro-31-8220, inhibited TNFα production from both activated T cell membrane- and LPS-stimulated monocytes to the same extent (in the range of 50–100% inhibition). Therefore, the activated T cell membrane–monocyte contact bioassay can be used to screen small molecule antagonists that specifically target adaptive but not LPS-mediated innate immunity. Small molecule TNFα inhibitors interfering specifically with activated T cell contact-mediated TNFα production from monocytes, but not with LPS-mediated TNFα production of myeloid cells, are predicted to have an improved side-effect profile and thus may provide more favorable therapeutics for the treatment of T cell-mediated inflammatory diseases. [Copyright &y& Elsevier]

Psoriasis, atopic dermatitis and allergic contact dermatitis are T-cell-mediated inflammatory skin diseases; chemokine receptors (CCR) 4 and 10 play an important role in the ligand-mediated recruitment of T cells into the skin in mice and humans, specifically with regards to tethering, firm adhesion and subsequent extravasation to the sight of injury. We utilized established murine models of dinitrofluorobenzene-, trimellitic acid anhydride- or oxazalone-induced contact hypersensitivity, to reflect the various Th-polarizations of different skin diseases, and investigated the functional effect of antibody blocking of single CCR ligands or combination therapy to block all CCR4 and CCR10 ligands. Our results indicate a greater reduction in inflammatory response – measured by oedema formation, myeloid cell and neutrophil infiltration and activity and CD3+ cell infiltration at the site of injury – with combination antibody therapy to CCR4 and CCR10 ligands versus controls, in nearly every tested condition. We conclude that blocking CCR4 and CCR10 simultaneously, or their ligands, should be beneficial in the treatment of T-cell-mediated skin diseases. [ABSTRACT FROM AUTHOR]