title: Mechanisms of cyclosporine A inhibition of antigen-presenting activity in uninvolved and lesional psoriatic epidermis.
abstract: To elucidate how cyclosporine A affects antigen-presenting cell subsets and their function in human skin, we studied patients with psoriasis undergoing a therapeutic trial of cyclosporine A. Immunologic parameters abnormal in psoriatic epidermis were evaluated before and early in the course of therapy. We quantitated function and numbers of skin biopsy-derived epidermal cells with potential antigen-presenting cell (APC) activity. The antigen-presenting capacity of epidermal cells from normal-appearing skin to activate allogeneic T cells was profoundly inhibited (81% decrease) 7 d after the onset of therapy (p less than 0.05). Thus, cyclosporine A therapy inhibited T-cell activation mediated by Langerhans cells in uninvolved skin. By contrast, in lesional skin epidermal allo-antigen presenting activity was only partially inhibited at this early time point (55 +/- 7% decrease) (p less than 0.01, n = 8). The percentage decrease in allo-antigen-presenting cell activity correlated with reduced clinical activity of the lesions, r = 0.84. In three patients also examined at 14 d, we found an additional 42 +/- 5% decrease between day 7 and 14. Decreased allo-antigen-presenting activity in lesional skin was not associated with a decrease in the number of CD1+ Langerhans cells or epidermal cell release of detectable amounts of cyclosporine A or other soluble factors that abrogate T-cell alloreactivity. The time course and degree of inhibition of antigen-presenting capacity within involved psoriatic skin correlated best with a significant (p less than 0.01) reduction in non-Langerhans cell DR+ leukocytes (from 3.0 +/- 1.2% to 1.0 +/- 0.6% at day 7) (r = 0.71). Cyclosporine A therapy was associated with a rapid and complete loss of HLe1-DR+ keratinocytes (94% decrease at 7 d) in lesional skin despite the skin still being quite involved with psoriasis at this point and antigen-presenting cell activity being only 60% reduced. In conclusion, cyclosporine A interferes with T-cell activation by human epidermis through at least two mechanisms: 1) in uninvolved skin, rapid inhibition of Langerhans cell-mediated activation of T cells, and 2) in lesional skin, delayed inhibition of antigen-presenting activity which appears to correlate with the time course and level of reductions in non-Langerhans cell DR+ leukocytes. The antigen-presenting activity of the latter cells appears to be cyclosporine A resistant. In psoriatic lesions, early and complete loss of DR expression on lesional keratinocytes during cyclosporine A therapy is likely due to decreased lesional T-cell lymphokine production critical for keratinocyte DR expression.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Anne Arbor 48109-0530.
authors.forename: K D
authors.initials: KD
authors.lastname: Cooper
authors.forename: O
authors.initials: O
authors.lastname: Baadsgaard
authors.forename: C N
authors.initials: CN
authors.lastname: Ellis
authors.forename: E
authors.initials: E
authors.lastname: Duell
authors.forename: J J
authors.initials: JJ
authors.lastname: Voorhees
mesh_terms: D000938:Antigen-Presenting Cells / Q000187:drug effects*; D002452:Cell Count; D003524:Cyclosporins / Q000494:pharmacology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D015603:Keratinocytes / Q000276:immunology; D007801:Langerhans Cells / Q000166:cytology; D008213:Lymphocyte Activation; D008297:Male; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000276:immunology
chemical_list: D003524:Cyclosporins; D006684:HLA-DR Antigens