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Title: Immunological studies into the mechanisms of action of cyclosporin A in psoriasis
Author: Horrocks, C.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1992
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Seven chronic plaque psoriasis patients were treated with cyclosporin A (CsA, 2.5-5.0 mg/kg/day). A marked resolution of psoriasis was observed within 4 weeks of treatment. Immunophenotypic analysis of patients' peripheral blood mononuclear cells (PBML) before and during CsA therapy revealed no difference in comparison to normal nor any change following CsA therapy. Immunocytochemical analysis of lesional skin, however, revealed marked reductions in infiltrating CD3+ (pan T), CD4+ (T helper), CD25+ (interleukin 2 receptor) and to a lesser extent CD8+ (T cytotoxic/suppressor) cells within 4 weeks of CsA therapy. These data may indicate a preferential depletion of activated lesional T cells by CsA. Lesional epidermal CD1+ (Langerhans cells) numbers were reduced in comparison to normal skin whilst dermal CD1+ cells were increased. CsA treatment normalised both the distribution and frequency of CD1+ cells in the lesions. In normal epidermis CD29 was the only adhesion molecule detected and was confined to basal keratinocytes (KC). In addition to CD29, lesional KC also expressed LFA-3 and CD11c which were unaffected by CsA therapy. The dermal infiltrate and blood vessels were strongly positive for ICAM-1 and HLA-DR (both reduced by CsA) whilst no staining was observed on KC. In addition to EGFR (epidermal growth factor receptor) and CK10+ 11 (cytokeratin), which are expressed in normal epidermis, lesional epidermal keratinocytes were also found to express the hyperproliferation marker C13+ 16. Neither EGFR nor CK expression was altered during CsA therapy. Normal human keratinocyte proliferation in vitro was inhibited by both CsA (6-10 μg/ml) and IFNγ (25-200 U/ml) which was accompanied by decreased EGFR expression, measured by flow cytometry, and a paradoxical increase in KC TGFα production. IFNγ, but not CsA, was also able to induce KC ICAM-1 expression. The inhibitory effects of CsA on cultured KC occurred at concentrations greater than those reported in the lesions of CsA treated psoriatics and therefore the anti-psoriatic effect of CsA is probably mediated via inhibition of lesional T cell function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available