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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]

Abstract: The pleiotropic functions of tumor necrosis factor-alpha (TNFα) have brought considerable attention in the past decade to its physiological and pathological roles in inflammatory and autoimmune diseases. However, little is known about how the production of TNFα is regulated at the transcriptional and translational levels in immune cells such as T and B lymphocytes. Our previous study demonstrated that unspliced “pre-mRNA” of TNFα is present in resting T cells. Initiation of splicing of TNFα pre-mRNA to mature mRNA requires T cell activation, which is unique and necessary for TNFα production when compared to its production in mononuclear phagocytes, including different lineages of macrophages (Mϕ) and dendritic cells (DC). In this study, we further demonstrate that resting mouse B cells also contain pre-existing TNFα mRNA. The physiological process of B cell activation induced by (1) either the cross-linking of the B cell receptor (BCR) or CD40, (2) treatment with LPS, or PMA plus ionomycin, induces TNFα mRNA splicing in vitro. The kinetic response of TNFα splicing in B cells is much slower when compared to that in activated T cells. Studies using well-known kinase inhibitors demonstrated that MAP kinase kinase (MEK) and protein kinase C (PKC) are required for TNFα splicing upon stimulation through the BCR. These studies demonstrate that the production of TNFα in activated B cells is regulated differently than in activated T cells, and these differences may allow for the selective inhibition of TNFα in various autoimmune diseases depending on the mechanism of action of the selected anti-TNFα therapy. [Copyright &y& Elsevier]