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Abstract: Tissue-selective recruitment of immunocytes to cutaneous tissues, a complex multistep cascade mediated by a large variety of cytokines, chemokines, and adhesion molecules, is thought to be a pivotal process in the pathogenesis of psoriasis. Following this notion, specifically targeting leukocyte trafficking remains an attractive approach for the treatment of psoriasis. It is increasingly recognized that during the pathogenesis of psoriasis not only effector T cells play important roles, but also multiple interactions between T cells, dendritic cells, macrophages, mast cells, endothelial cells, and keratinocytes are crucial for the full-fledged development of psoriasis. Meanwhile, the first biologics specifically inhibiting key molecules involved in cutaneous leukocyte recruitment have been approved for the treatment of psoriasis. It is, however, challenging to predict that molecules in this complex process with many redundant and/or functionally overlapping players will suffice as therapeutic targets. In this review, we will discuss the molecules and mechanisms involved in trafficking of different types of leukocytes and elucidate modes of action as well as therapeutic strategies of existing drugs and drug candidates. [Copyright &y& Elsevier]

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]