Effects of novel immunosuppressive agents on adhesion molecule expression and cell-mediated immune responses
The specific anti-T lymphocyte immunosuppressive drugs cyclosporine A (CsA), FK-506 (FK) and rapamycin (RPM) have revolutionized the field of allograft transplantation and have recently been evaluated for use in autoimmune diseases. Effects of immunosuppressive drugs on adhesion molecule expression in the putative autoimmune conditions psoriasis, through the use of keratinocyte (KC) cell culture techniques, and alopecia areata were investigated. In the Dundee Experiment Bald Rat, a model of alopecia areata, hair regrowth was only apparent with CsA therapy and FK had a high toxicity profile. In vivo the observed cutaneous reduction of ICAM-1 and LFA-1 expression particularly around the hair bulbs was due to the effects of CsA and FK on the inflammatory cell infiltrate, especially since the associated cutaneous lymphocyte populations were reduced with drug. This is corroborated by the results obtained from in vitro culture of human KC, since cytokine-induced expression and release of ICAM-1 by KC was unaffected by CsA, RPM or FK treatment. CsA and RPM, but not FK, however, had an observable cytostatic effect on unstimulated and more especially, cytokine-stimulated KC proliferation and may, therefore, clinically inhibit KC hyperplasia, which is characteristic of psoriasis. This study shows that CsA, FK and RPM may inhibit either directly but more likely in an indirect manner, cellular adhesion molecule expression during immune reactions. This effect will lower the possible number of cellular interactions and furthermore, reduce intracellular co-signalling events necessary for cellular activation which accounts for the overall inhibition of cell-mediated immune responses by these novel immunosuppressive drugs.