Cilomilast, tacrolimus and rapamycin modulate dendritic cell function in the elicitation phase of allergic contact dermatitis.
BACKGROUND
Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis.


OBJECTIVE
To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor cilomilast with those of tacrolimus and rapamycin.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Bäumer
W
W
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany. wolfgang.baeumer@tiho-hannover.de
Sülzle
B
B
Weigt
H
H
De Vries
V C
VC
Hecht
M
M
Tschernig
T
T
Kietzmann
M
M
D000818:Animals; D039521:CD11c Antigen / Q000032:analysis; D002264:Carboxylic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000276:immunology* / Q000473:pathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007801:Langerhans Cells / Q000187:drug effects; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D012867:Skin / Q000201:enzymology / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
D039521:CD11c Antigen; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D009570:Nitriles; C433247:Cilomilast; D020780:Matrix Metalloproteinase 9; D020123:Sirolimus; D016559:Tacrolimus