sirolimus and Dermatitis--Contact

Topics: Animals; Anti-Bacterial Agents; Carrier Proteins; Cyclosporine; Dermatitis, Atopic; Dermatitis, Contact; Disease Models, Animal; Guinea Pigs; Immunosuppressive Agents; Mice; Polyenes; Receptors, Drug; Receptors, Immunologic; Sirolimus; Swine; Tacrolimus; Tacrolimus Binding Proteins

Ultraviolet radiation induces signal transduction at both early (<6 h) and late (>6 h) times after exposure. The inflammatory and immunosuppressive cytokine tumor necrosis factor alpha is induced at late times, and is induced by ultraviolet-induced DNA damage, as defects in DNA repair increase, and enhanced photoproduct repair reduces, tumor necrosis factor alpha expression. Here we show that late tumor necrosis factor alpha gene expression is sensitive to rapamycin, implicating FKBP12-rapamycin-associated protein, a member of the DNA protein kinase family, as a signal transducer of ultraviolet-induced DNA damage. FKBP12-rapamycin-associated protein was localized in the nucleus of keratinocytes and its level was increased following ultraviolet irradiation. Immuno- precipitated FKBP12-rapamycin-associated protein was stimulated by ultraviolet-irradiated DNA to phosphorylate p53 in vitro, and in vivo rapamycin reduced ultraviolet induction of p53 by 20%. Rapamycin further inhibited the ultraviolet-induced phosphorylation of the FKBP12-rapamycin-associated protein downstream target kinase p70S6K. In mice, topical application of rapamycin before ultraviolet exposure protected against suppression of the contact hypersensitivity that is a hallmark of ultraviolet-induced cytokine gene expression. These results demonstrate that the FKBP12-rapamycin-associated DNA protein kinase transduces the signal of ultraviolet-induced DNA damage into production of immunosuppressive cytokines at late times after ultraviolet irradiation.

Topics: Dermatitis, Contact; DNA; DNA Damage; DNA-Activated Protein Kinase; DNA-Binding Proteins; Fluorescent Antibody Technique; Humans; Immunophilins; Nuclear Proteins; Phosphorylation; Precipitin Tests; Protein Serine-Threonine Kinases; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Tacrolimus Binding Proteins; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Ultraviolet Rays

We have evaluated the effects of three potent immunosuppressive agents, cyclosporin A (CsA), FK506 and rapamycin, on the murine contact sensitivity (CS) reaction to the hapten trinitrochlorobenzene. Development of CS reaction requires participation of three distinct T cell subsets: alphabeta+, CD4+ T lymphocytes, which are the classical effector cell of the CS reaction, gammadelta+ T lymphocytes, and alphabeta+, double-negative (CD4- CD8-) T lymphocytes that express the B220 molecule and produce IL-4. We found that all three drugs inhibit the development of the CS reaction, but they affect different target cells. In fact, rapamycin and FK-506 block both alphabeta+, CD4+ and gammadelta+ T lymphocytes, while CsA inhibits only the alphabeta+, CD4+ T lymphocyte. None of the three drugs exerted any inhibitory activity on the alphabeta+, double-negative (CD4- CD8-) T lymphocytes. Hapten-immune lymph node cells from mice treated in vivo with CsA or FK506 failed to proliferate and to produce IL-2 when re-exposed to the specific antigen in vitro. In contrast, immune lymph node cells from mice that had been treated in vivo with rapamycin gave optimal antigen-specific proliferation and IL-2 production in vitro. The implications of these observations are discussed in relation to the use of these immunosuppressive agents for prevention of allograft rejection.

Topics: Animals; Cyclosporine; Dermatitis, Contact; Immunosuppressive Agents; Lymphocyte Activation; Male; Mice; Mice, Inbred CBA; Picryl Chloride; Polyenes; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Sirolimus; T-Lymphocyte Subsets; Tacrolimus

The immunosuppressive macrolide antibiotics FK 506 and rapamycin were tested for topical activity in experimental allergic contact dermatitis of farm pigs. This species was used because pig skin, in comparison to rodent skin, resembles human skin more closely. For comparison, cyclosporine A (CyA), which is orally but not topically active in patients with skin disease, dexamethasone, and clobetasol propionate were used. Treatment was performed twice, 30 min and 6 h after elicitation of challenge reaction. Topical application of 0.4 to 0.04% FK 506 caused a pronounced inhibition of inflammatory skin reactions of hypersensitivity to dinitrofluorobenzene. The treatment response was similar to the activity of 0.13% clobetasole. Dexamethasone (1.2%) was less active than clobetasol. In contrast, rapamycin and CyA were inactive at concentrations of 1.2 and 10%, respectively. Because the pig data on corticosteroids and cyclosporine A are in agreement with clinical findings, these studies indicate that immunosuppressive macrolides of the type FK 506 may be useful drugs for the topical treatment of human skin diseases that respond to local corticosteroids and oral treatment with cyclosporine A.

Topics: Animals; Clobetasol; Cyclosporine; Dermatitis, Contact; Dexamethasone; Disease Models, Animal; Female; Molecular Structure; Polyenes; Sirolimus; Swine; Tacrolimus