Commentary 2

Abstract

The detailed knowledge on the mechanisms leading to leukocyte recruitment into the skin has led to the identification of new potential targets for the therapy of chronic inflammatory skin diseases such as psoriasis and atopic dermatitis (1). Many compounds with antagonistic properties on leukocyte–endothelial cell interactions have been developed. Compared to conventional immunosuppressive therapies, strategies aimed to interfere specifically with leukocyte extravasation may have several relevant advantages. In fact, this approach could block the recruitment of leukocytes selectively into the skin, thus allowing efficient immune responses in other districts and preserving protection to new antigens. Ideally, this therapy should block exclusively the recruitment of pathogenic T cells. In contrast, the entrance into the skin of T-cell subsets with regulatory activity should not be inhibited as they function as natural suppressant of immune responses (2, 3). A major limitation of targeting leukocyte accumulation in the skin is the high complexity of the molecules involved in this process. This means that blocking a single molecule may not be sufficient for effective reduction of inflammation and that multiple molecules should be inhibited to obtain a clinically relevant effect. Major targets proposed so far include selectins, chemokine-chemokine receptor pairs, as well as integrins (Fig. 1). Potential strategies to interfere with selectin functions include blocking Abs, transcriptional regulation of selectin expression, and modulation of the post-trascriptional glycosylation of selectin ligands, such as the administration of fluorinated antagonists, which interfere with the synthesis of the cutaneous lymphocyte antigen (CLA) (4, 5). Although effective in murine models of inflammation, the therapeutic activity of compounds blocking only one selectin in humans has been disappointing (6). Indeed, many small-molecule inhibitors of the selectin family have been abandoned because of their ineffectiveness in phase I-II clinical trials (1). Therapeutic failure appears as a consequence of the high level of promiscuity and redundancy of the selectin system, with most of the functions of either E- or P-selectins largely overlapping, and L-selectin-mediated rolling taking over when the others are inhibited. For this reason, new molecules, such as Efomycine M, which blocks multiple selectins may have a higher chance of success (7). Finally, T-regulatory cells (both T-regulatory cells 1 and CD4+CD25+ T cells) homing to the skin are invariably CLA+ (2, 3). Molecules implicated in leukocyte recruitment in the skin and potential targets of therapeutic intervention in chronic inflammatory skin diseases: 1. endothelial cell selectins, which mediate tethering and rolling of leukocytes; 2. chemokine receptors on leukocytes (e.g. CCR4 and CCR10), whose engagement induces integrin activation; and 3. integrins, which are responsible for firm adhesion that precedes leukocyte extravasation. Leukocytes are then attracted into the dermal and epidermal compartments by gradients of chemokines produced by resident and immigrated cells and maintained in situ by adhesion molecules. Integrins are also involved in T-cell activation and retention in the epidermis Among chemokine receptors, two candidates for skin-specific leukocyte extravasation have been identified: CCR4 and CCR10 (8, 9). CCR4 is expressed on most CD4+CLA+ T cells, independently from the cytokine polarization and represents a suitable target for skin recruitment blockade with small-molecule compounds. However, CCR4 expression is not exclusive for skin-homing lymphocytes, with T-lymphocytes homing in the respiratory tract enriched for CCR4+ cells. Moreover, CCR4 is poorly expressed on CD8+ T cells, which have a major effector function in allergic contact dermatitis and possibly in psoriasis (10). CCR10 is certainly more specific for T cells engaged in the skin, being virtually absent from T cells migrating in other districts. However, only a minor portion of CLA+CCR4+ T cells coexpress the CCR10 (11). Indeed, it has been shown in mouse that inhibition of CCL27 (CC-chemokine ligand) blocked skin homing of T cells in CCR4–/–, but not in wild-type mice (12). Approaches aimed at targeting integrins appear so far the most promising. Experimental data indicate that blocking the CD18 (β2 chain of leukocyte function-associated antigen-1) is strongly effective in reducing the expression of contact hypersensitivity in mice (13), and other compounds, such as efalizumab (anti-CD11a), alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide), and natalizumab (anti-VLA-4 (very late antigen)), have already entered clinical trials for psoriasis and other autoimmune diseases with satisfactory results (14-16). In addition to their capacity to reduce T-cell adhesion to endothelium, most of integrin antagonists affect T-cell activation to a certain degree, thus augmenting the chance of therapeutic effectiveness in immune-mediated disorders.