IL15 in Psoriasis and Psoriatic Arthritis

IL-15 exhibits a plausible bioactivity profile in skin inflammation and has been detected in high levels in a range of inflammatory dermatoses. Thus, keratinocytes express both IL-15 and IL-15Ra, suggesting a role in autocrine regulation of keratinocytes in dermal inflammatory responses (Ruckert et al. 2000). Dermal IL-15 is upregulated by UVB irradiation and overexpression is associated with cutaneous malignancy (Mohamadzadeh et al. 1995). IL-15 has also been reported in bullous lesions, post-burn injury and in chronic cutaneous infection (Ameglio et al. 1999; Castagnoli et al. 1999). Whereas reduced levels are reported in atopic dermatitis that has been associated with propensity to enhanced Th2-mediated inflammation, increased IL-15 expression is consistently reported in psoriatic lesions (Ruckert et al. 2000; Ong et al. 2002). Psoriatic dermal pathology is characterised by local T cell, macrophage and neutrophil infiltration and activation, angiogenesis and epidermal hyperplasia, all features to which IL-15 may plausibly contribute. Prior studies associated dermal IL-15 with reduction in keratinocyte apopto-sis together with promotion of T cell activation (Ruckert et al. 2000). Further insight as to the mechanisms whereby IL-15 mediates such effects emerged using the keratinocyte cell line HaCaT (Yano et al. 2003). IL-15-enhanced HaCaT proliferation was sensitive to addition of the MEK inhibitor U0126 or PI3-K inhibitor, LY294002. Erk1/2 and Akt phosphorylation, but not JNK, p38, STAT1 or STAT3, were observed in IL-15-treated epidermal cells andUVB-induced apoptosis was reversed. These data suggest that IL-15-mediated rescue from apoptosis previously observed in T cells could operate to promote epidermal proliferation in psoriasis. Complex interactions between T cells and keratinocytes mediated via cytokine networks including the Fas/FasL pathways have been proposed (Arnold et al. 1999). Similarly, direct IL-15-dependent interactions between skin fibroblasts and T cells have been proposed whereby TNF-exposed dermal fibroblasts upregulate membrane IL-15 to thereby activate adjacent T cells and suppress their apoptosis (Rappl et al. 2001). Thus TNFa and IL-15 cross-regulation of local inflammation is likely.

We extended these studies in an arthroscopic study of synovial membranes obtained prior to and after methotrexate therapy for 3 months. These studies showed that IL-15 mRNA and protein were modified but not abrogated by methotrexate treatment, raising the possibility that IL-15 targeting together with methotrexate might be reasonable (Kane et al., personal communication).

In vivo data suggesting a role for IL-15 first emerged in the psoriasis SCID model. A psoriatic patient derived CD94+/CD161+ T cell line injected into prepsoriatic skin engrafted on SCID mice induced development of psoriaform lesions characterised by local cytokine production. This cytokine network was of Th1 phenoytpe and predominated by IFNy and IL-15 expression (Nickoloff et al. 2000). Definitive preclinical evidence for a pro-inflammatory role for IL-15 in psoriasis was subsequently derived using a human anti-IL-15 monoclonal antibody (146B7, Humax-IL15 above, now termed AMG714) raised in a human immunoglobulin transgenic in a xenograft murine model (Villadsen et al. 2003). AMG714 bound IL-15Ra that was in turn bound to IL-15 and in vitro, effectively neutralised IL-15-mediated lymphocyte reversal of apoptosis and pro-inflammatory cytokine release. Thereafter, human psoriatic skin (shown to express IL-15) was grafted onto SCID mice that in turn were treated with AMG714, cyclosporin or PBS. Significant reduction in histologic score, epidermal thickness, mononuclear infiltration, grade of parakeratosis and of keratinocyte cycling (via ki67 staining) were observed compared with either CyA or PBS-treated control grafts. These data are of importance for two reasons. They functionally implicate IL-15 in psoriatic pathogenesis. Moreover, they demonstrate for the first time the efficacy in vivo of antibody-mediated IL-15 neutralisation. Importantly, AMG714 apparently functions without interfering with IL-15:IL-15Ra interactions, operating through a nonclassical neutralisation pathway that allows blockade of the activities of prebound IL-15. This will theoretically facilitate interactions operating both on cis- and trans-configured IL-15Ra|3y complexes (Dubois et al. 2002).

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