TOPICAL FK506 SUPPRESSES CYTOKINE AND COSTIMULATORY MOLECULE EXPRESSION IN EPIDERMAL AND LOCAL DRAINING LYMPH-NODE CELLS DURING PRIMARY SKIN IMMUNE-RESPONSES

Recently, it has been shown that the immunosuppressive macrolide lacto ne, FK506, exerts good therapeutic efficacy in inflammatory skin disea ses. The aim of this study was to analyze the influence of topical FK5 06 on molecular (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-12 p35, IL-12 p 40, macrophage inflammatory protein-2 (MIP-2), granulocyte-macrophage CSF (GM-CSF), TNF-alpha, and IFN-gamma) and cellular (I-A(+)/CD80(+), I-A(+)/CD54(+), I-A(+)/CD69(+), I-A(+)/B220(+), and CD4(+)/CD25(+)) ev ents in epidermal (EC) and local draining lymph node (LNC) cells durin g primary contact hypersensitivity responses. Cytokine mRNA levels for IL-1 alpha, IL-1 beta, GM-CSF, TNF-alpha, MIP-2, and IFN-gamma in EC and for IL-2, IL-4, IL-12 p35, IL-12 p40, and IFN-gamma in LNC were in creased and resulted in significant LNC proliferation during oxazolone -induced contact hypersensitivity. Topical FK506 treatment dose-depend ently suppressed oxazolone-induced LNC proliferation. This effect was correlated with decreased IL-1 alpha, IL-1 beta, GM-CSF, TNF-alpha, MI P-2, and IFN-gamma mRNA expression within the epidermis and decreased IL-12 p35 and p40 mRNA expression in LNC. Further analysis of the LNC cytokine pattern revealed that the production of both Th1 (IFN-gamma a nd IL-2) and Th2 (IL-4) cytokines was dramatically impaired after topi cal FK506 treatment. Flow cytometric analysis showed that topical FK50 6 decreased the population of epidermis-infiltrating CD4(+) T cells an d suppressed the expression of CD54 and CD80 on I-A(+) EC and LNC duri ng hapten-induced contact hypersensitivity. Furthermore, topical FK506 profoundly impaired oxazolone-induced up-regulation of CD25 expressio n on CD4(+) LNC and dramatically decreased hapten-induced expansion of I-A(+)/B220(+) and I-A(+)/CD69(+) LNC subsets. In conclusion, these r esults give new insights into the mechanisms of action of topical FK50 6 treatment.