sirolimus and Dermatitis--Allergic-Contact

Allergic contact dermatitis (ACD) is a common T-cell mediated inflammatory skin condition, characterized by an intensely pruritic rash at the site of contact with allergens like poison ivy or nickel. Current clinical treatments use topical corticosteroids, which broadly and transiently suppress inflammation and symptoms of ACD, but fail to address the underlying immune dysfunction. Here, we present an alternative therapeutic approach that teaches the immune system to tolerate contact allergens by expanding populations of naturally suppressive allergen-specific regulatory T cells (Tregs). Specifically, biodegradable poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) microparticles were engineered to release TGF-β1, Rapamycin, and IL-2, to locally sustain a microenvironment that promotes Treg differentiation. By expanding allergen-specific Tregs and reducing pro-inflammatory effector T cells, these microparticles inhibited destructive hypersensitivity responses to subsequent allergen exposure in an allergen-specific manner, effectively preventing or reversing ACD in previously sensitized mice. Ultimately, this approach to in vivo Treg induction could also enable novel therapies for transplant rejection and autoimmune diseases.

Topics: Allergens; Animals; Cell Differentiation; Dermatitis, Allergic Contact; Female; Immune Tolerance; Interleukin-2; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Transgenic; Polyesters; Polyethylene Glycols; Sirolimus; T-Lymphocytes, Regulatory; Transforming Growth Factor beta1

Topics: Administration, Cutaneous; Adult; Chemotherapy, Adjuvant; Dermatitis, Allergic Contact; Female; Humans; Immunosuppressive Agents; Laser Therapy; Port-Wine Stain; Sirolimus

Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis.. To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor cilomilast with those of tacrolimus and rapamycin.. The in vitro action of cilomilast, tacrolimus and rapamycin were tested in a mixed leucocyte reaction (MLR). In vivo, the inhibitory action of the immunomodulatory drugs was compared in the toluene-2,4-diisocyanate (TDI)-induced allergic inflammatory response with particular focus on dendritic cell (DC) function.. Cilomilast, tacrolimus and rapamycin were all able to inhibit DC-mediated T-cell activation in a MLR. But it was demonstrated for cilomilast that the target cells are T cells rather than DC. In vivo, a combination of systemic and topical administration of each of these three substances significantly inhibited swelling in the murine ear 16 h after TDI challenge. There was also a reduction in the weight of the draining auricular lymph node, in lymphocyte cell count, and in the number of emigrated DC. The density of Langerhans cells in the epidermis was correspondingly higher in mice treated with cilomilast, tacrolimus and rapamycin than in those treated with vehicle. All three substances were found to inhibit DC migration ex vivo in a skin DC migration assay performed on ear tissue after TDI challenge.. DC migration into the draining lymph node also takes place in the elicitation phase of allergic contact dermatitis and this migration can be influenced by tacrolimus and rapamycin, and, to a lesser extent, by cilomilast.

Topics: Animals; Carboxylic Acids; CD11c Antigen; Cells, Cultured; Cyclohexanecarboxylic Acids; Cytokines; Dendritic Cells; Dermatitis, Allergic Contact; Female; Histocompatibility Antigens Class II; Immunosuppressive Agents; Langerhans Cells; Leukocyte Count; Lipopolysaccharides; Lymph Nodes; Lymphocyte Culture Test, Mixed; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Nitriles; Organ Size; Sirolimus; Skin; Tacrolimus

Activation and skin-selective homing of T cells and effector functions in the skin represent sequential events in the pathogenesis of atopic dermatitis and allergic contact dermatitis.. T cell-mediated keratinocyte apoptosis plays a key pathogenetic role in the formation of eczematous dermatitis. IFN-gamma released from activated T cells upregulates Fas on ke-ratinocytes, which renders them susceptible to apoptosis. The lethal hit is given to keratinocytes by means of Fas ligand expressed on the T-cell surface or released to the inflammatory microenvironment. We sought to investigate whether drugs used for the treatment of eczematous disorders interfere with this pathogenic pathway.. T cell-mediated, Fas-induced keratinocyte apoptosis in a keratinocyte-T cell coculture system serves as an in vitro model of eczematous dermatitis. We tested, in this model, whether immunomodulatory agents (dexamethasone, cyclosporine A, rapamycine, tacrolimus/FK506, intravenous immunoglobulin [IVIG], and theophylline) are able to inhibit apoptosis of keratinocytes. Additionally, skin biopsy specimens from patients with untreated and successfully treated eczematous dermatitis were evaluated for keratinocyte apoptosis.. Dexamethasone, cyclosporine A, FK506, rapamycine, and IVIG are inhibitors of keratinocyte apoptosis induced by activated T cells. This effect is mediated by 2 major mechanisms directed on T cells or keratinocytes. T-cell activation was mainly inhibited by dexamethasone, FK506, cyclosporine A, and rapamycine. Interestingly, high-dose dexamethasone and IVIG directly inhibited Fas-mediated keratinocyte apoptosis. In vivo keratinocyte apoptosis was significantly reduced after successful topical treatment of eczematous lesions.. These results demonstrate mechanisms of action of current treatment approaches and provide a future for more focused therapeutic applications.

Topics: Acute Disease; Apoptosis; Cells, Cultured; Cyclosporine; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dexamethasone; fas Receptor; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interleukin-12; Keratinocytes; Sirolimus; T-Lymphocytes; Tacrolimus; Th1 Cells; Theophylline