Effects of calcineurin inhibitors on an in vitro assay for chronic urticaria.
BACKGROUND
Chronic urticaria is a common skin disorder, which causes considerable morbidity. In approximately 40% of cases, patients have an autoimmune disorder in which functional antibodies cause degranulation of mast cells and basophils, and C5a complement augments this in varying amounts from patient to patient. Since the calcineurin inhibitor ciclosporin has been used in chronic autoimmune urticaria, we examined the effect of ciclosporin and other drugs on the release of histamine from basophils when stimulated by sera from patients with chronic autoimmune urticaria.


METHODS
Leucocytes from healthy donors were isolated and incubated in varying concentrations of ciclosporin, ascomycin, methotrexate, diphenhydramine or hydroxyzine for 30 min prior to stimulation with serum from urticaria patients known to have functional immunoglobulin (Ig)G antibodies directed against the alpha subunit of the IgE receptor. Histamine release was then measured.


RESULTS
Pre-incubating cells with ciclosporin and ascomycin produced dose-dependent inhibition of histamine release when cells were stimulated by sera of urticaria patients, by purified IgG from these sera, but not by C5a. Inhibition was not prevented by C5a receptor blocking antibodies. No inhibition was seen with methotrexate, diphenhydramine or hydroxyzine.


CONCLUSIONS
This is the first demonstration of inhibition of histamine release by calcineurin inhibitors employing sera of patients with chronic autoimmune urticaria. These drugs may work by interfering with intracellular signalling in cells following cross-linking of the IgE receptor, but not following stimulation of the C5a receptor.
Marsland
A M
AM
Department of Medicine, Division of Pulmonary and Critical Care, Allergy and the Clinical Immunology and the Konishi-MUSC Institute for Inflammation Research, Medical University of South Carolina, Charleston, SC 29425, USA.
Soundararajan
S
S
Joseph
K
K
Kaplan
A P
AP
D001491:Basophils / Q000276:immunology; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D002908:Chronic Disease; D015936:Complement C5a / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use*; D004155:Diphenhydramine / Q000627:therapeutic use; D004306:Dose-Response Relationship, Immunologic; D006634:Histamine H1 Antagonists / Q000627:therapeutic use; D006636:Histamine Release / Q000276:immunology; D006801:Humans; D006919:Hydroxyzine / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007962:Leukocytes / Q000276:immunology; D008727:Methotrexate / Q000627:therapeutic use; D012008:Recurrence; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D014581:Urticaria / Q000188:drug therapy* / Q000276:immunology
D065095:Calcineurin Inhibitors; D006634:Histamine H1 Antagonists; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D006919:Hydroxyzine; D015936:Complement C5a; D016572:Cyclosporine; D004155:Diphenhydramine; C058028:immunomycin; D016559:Tacrolimus; D008727:Methotrexate