Topical tacrolimus and cyclosporin A differentially inhibit early and late effector phases of cutaneous delayed-type and immunoglobulin E hypersensitivity.
Systemic and topical administration routes of tacrolimus and cyclosporin A (CsA) were compared in effects on early and late phases of elicited T-cell-mediated contact sensitivity (CS), and effects on early and late phases of cutaneous immunoglobulin E (IgE) antibody-mediated hypersensitivity responses in mice. Thus, both CS and IgE responses in the skin have an early mast-cell-dependent phase, and also a late inflammatory phase. We measured the effects of both immunosuppressants on both phases of the respective T cell versus IgE responses. Systemic administration of both agents completely suppressed CS and IgE late-phase responses, but failed to affect either early phase. In contrast, when topical CsA was used, low doses abolished the early phase of IgE responses, but even high doses did not inhibit the early phase of CS. Conversely, topical tacrolimus inhibited the early phase of CS more potently than the early phase of cutaneous IgE hypersensitivity responses. Thus, topical treatment was needed to inhibit the early phases and the two agents acted differentially, suggesting differing susceptibility of the early phases, that are probably due to different signalling mechanisms. These studies underscore the potential value of topical administration of these powerful immunosuppressive agents in the treatment of allergic diseases that exhibit features of early-phase mast-cell-dependent inflammation, and late inflammation due to mast cells or to T cells, such as atopic dermatitis or asthma, since the early phase is predominantly susceptible to topical application, while the last phase of both IgE and T-cell inflammation responds to systemic treatment with both agents.
Geba
G P
GP
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8057, USA.
Ptak
W
W
Askenase
P W
PW
D000279:Administration, Cutaneous; D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000517:prevention & control*; D003876:Dermatitis, Atopic / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010853:Picryl Chloride / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D007073:Immunoglobulin E; D016572:Cyclosporine; D016559:Tacrolimus; D010853:Picryl Chloride