tacrolimus and Dermatitis--Contact

Pimecrolimus (SDZ ASM 981), nonsteroid anty-inflammatory ackomycin-derived drug has more and more indications in dermatology. It has been recommended in therapy of atopic and contact dermatitis at the beginning. Nowadays pimecrolimus is used in the treatment of seborrhoic dermatitis, post-steroidal rosacea, bullous diseases etc. News reporting higher incidence of skin cancers after pimecrolimus application has not been proved clinically. The common use of mentioned medication forced us to detailed analysis of references concerning that problem.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Causality; Comorbidity; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Humans; Incidence; Skin Neoplasms; Tacrolimus

The newly developed immunomodulator tacrolimus (FK506) is the first of a new class of agents that have enormous potential to change the way that dermatoses are treated and managed. Tacrolimus has been found to be active in a topical formulation with the latter exerting its effects by acting on the signal transduction pathways inside T cells and inhibiting gene transcription. The result is decreased responsiveness of T cells to antigens. Percutaneous absorption of tacrolimus is higher in diseased skin as opposed to healthy skin and, therefore, the drug will be taken in at progressively lower quantities as lesions heal. There is limited systemic absorption of tacrolimus over the course of therapy. The most extensive experience with tacrolimus has been in treating atopic dermatitis. In numerous trials, tacrolimus ointment 0.03-0.3% has shown to be effective in reducing the symptoms and severity of atopic dermatitis in adults and the paediatric population. Furthermore, there have been no significant toxic effects associated with topical therapy with tacrolimus. The most common complaint is that of local irritation after applying the ointment. This is generally transient and the patient is able to continue with therapy. The other dermatoses where tacrolimus has been used include contact dermatitis, psoriasis and pyoderma gangrenosum.

Topics: Administration, Oral; Administration, Topical; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Female; Humans; Immunosuppressive Agents; Male; Prognosis; Psoriasis; Skin Absorption; Skin Diseases; Tacrolimus; Treatment Outcome

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams currently under development for the treatment of skin diseases. The main biological effect of ascomycins is an inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells. Several compounds are being developed with SDZ ASM 981 being at the most advanced stage. It has high anti-inflammatory activity in animal models of skin inflammation and does not induce skin atrophy. Topical application of SDZ ASM 981 was shown to be effective in atopic dermatitis (AD), allergic contact dermatitis and also in psoriasis under semi-occlusive conditions. In patients with AD, SDZ ASM 981 cream led to consistently low systemic exposure even when applied on large areas of skin. SDZ ASM 981 overcomes the drawbacks of current topical therapies of inflammatory skin diseases as its safety profile is better than that of topical corticosteroids. Studies continue to investigate its efficacy and safety in the treatment of inflammatory skin diseases.

Topics: Adult; Animals; Anti-Inflammatory Agents; Child; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Drug Evaluation, Preclinical; Humans; Models, Animal; Rats; Skin Diseases; Tacrolimus

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

Hand dermatitis is a chronic inflammatory skin disorder for which systemic immunosuppressive therapy is often needed. Topical treatments could complement the use of systemic corticosteroids.. To evaluate symptoms of hand dermatitis in subjects treated with a prednisone taper combined with topical tacrolimus 0.1% ointment versus vehicle.. Thirty-two subjects with moderate to severe hand dermatitis were enrolled in a randomized double-blind controlled trial. Subjects received a 3-week taper of prednisone and was randomized 2:1 to apply topical tacrolimus or its vehicle twice daily for 12 weeks. Disease severity was evaluated at baseline and at 5 follow-up visits (weeks 1-14). Any occurrence of relapse was recorded by patients.. Twenty-two of the 32 subjects (69%) had relapse of their disease. The mean time to recurrence for tacrolimus versus vehicle was 48 versus 39 days, respectively (P = .78). A greater improvement of induration (P = .003) and scaling (P = .003) for patients with tacrolimus compared to vehicle was detected, as well as subjective improvement (%) from week 1 to week 12 (P = .04) compared to vehicle. Improvement in erythema (P < .0001), fissuring (P = .0003), pruritus (P = .06), and investigator's global assessment (P < .0001) with tacrolimus was not found to exceed improvement with vehicle.. Small sample size provides limited power to detect differences in response.. Topical tacrolimus improves induration and scaling, and there is a trend suggesting it prolongs the time to recurrence.

Topics: Administration, Oral; Administration, Topical; Adult; Aged; Dermatitis, Atopic; Dermatitis, Contact; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Hand Dermatoses; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Tacrolimus

We identified 19 patients with facial atopic eczema who failed to respond to tacrolimus (FK506) ointment, although tacrolimus ointment has shown excellent benefit for the treatment of recalcitrant facial erythema in most patients with atopic dermatitis.. We attempted to determine the efficacy of an original lotion formulation of tacrolimus for facial atopic dermatitis resistant to tacrolimus ointment.. Recalcitrant facial erythema of these 19 patients was treated with an original tacrolimus lotion preparation for 6 months. Patch testing with white petrolatum was performed in both the 19 patients and in 30 other atopic dermatitis patients who had experienced excellent results with tacrolimus ointment.. Of the 19 resistant patients, those whose symptoms were greatly or moderately improved by the lotion were 95%, 89% and 89% after 2 weeks, 3 months and 6 months of treatment, respectively. Further, patch testing to petrolatum showed positive reactions in several (six of 19) patients, compared with none of 30 controls with atopic eczema that had responded to topical tacrolimus ointment.. The tacrolimus lotion had a significant effect on the recalcitrant facial erythema in adult patients with atopic dermatitis who were resistant to tacrolimus ointment. We suggest that one reason for the unresponsiveness to tacrolimus ointment may be because of contact sensitivity to white petrolatum.

Topics: Adolescent; Adult; Dermatitis, Atopic; Dermatitis, Contact; Dosage Forms; Drug Carriers; Drug Eruptions; Drug Resistance; Facial Dermatoses; Follow-Up Studies; Humans; Immunosuppressive Agents; Ointments; Patch Tests; Petrolatum; Tacrolimus

Topics: Administration, Cutaneous; Administration, Oral; Adult; Biopsy; Dermatitis, Contact; Dermatitis, Occupational; Drug Therapy, Combination; Facial Dermatoses; Glass; Humans; Male; Metronidazole; Minocycline; Ointments; Skin; Tacrolimus; Treatment Outcome

Topics: Administration, Cutaneous; Animals; Aprepitant; Behavior, Animal; Calcineurin Inhibitors; Dermatitis, Contact; Disease Models, Animal; Filaggrin Proteins; Ganglia, Spinal; Humans; Intermediate Filament Proteins; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ointments; Oxazolone; Oximes; Pruritus; Skin; Substance P; Tacrolimus; TRPA1 Cation Channel

Congenitally or early impaired skin barrier as the first event starting the 'atopic march' in atopic dermatitis (AD) patients can increase allergen penetration that results in sensitization, even in the airways, followed by asthma and allergic rhinitis. Thymic stromal lymphopoietin (TSLP) is a cytokine existing in high levels in AD skin and is considered as a novel therapeutic target for atopic disease. We generated oxazolone (Ox)-induced AD-like (Ox-AD) hairless mice and divided them into four groups according to the therapeutic challenges: topical glucocorticoid, pimecrolimus, emollient, and control (acetone-only treated). We assessed the functional studies of skin barrier, epidermal expressions of differentiation markers, IL-1α, TNF-α, proteinase-activated receptor-2 (PAR-2), TSLP and antimicrobial peptides (AMP), and serum IgE in each group. Topical glucocorticoid or pimecrolimus treatment improved AD-like skin lesions and barrier functions, and restored the epidermal expression of differentiation markers, IL-1α, TNF-α, PAR-2, and TSLP, in Ox-AD mice. The improvement was relatively better with the glucocorticoid than pimecrolimus. Epidermal AMP expression was restored by topical glucocorticoid, but not pimecrolimus. Our result showed that topical glucocorticoid or pimecrolimus improved the AD-like skin lesions and barrier impairment by suppressing TSLP-related allergic inflammation.

Topics: Adjuvants, Immunologic; Administration, Topical; Animals; Anti-Inflammatory Agents; Biomarkers; Cytokines; Dermatitis, Contact; Epidermis; Female; Gene Expression Regulation; Methylprednisolone; Mice; Mice, Hairless; Oxazolone; Permeability; Protein Precursors; RNA, Messenger; Tacrolimus; Thymic Stromal Lymphopoietin

Tinea incognito was first described 50 years ago. It is a dermatophytic infection with a clinical presentation modified by previous treatment with topical or systemic corticosteroids, as well as by the topical application of immunomodulators such as pimecrolimus and tacrolimus. Tinea incognito usually resembles neurodermatitis, atopic dermatitis, rosacea, seborrheic dermatitis, lupus erythematosus, or contact dermatitis, and the diagnosis is frequently missed or delayed.

Topics: Administration, Cutaneous; Antifungal Agents; Dermatitis, Atopic; Dermatitis, Contact; Dermatitis, Seborrheic; Dermatologic Agents; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lupus Erythematosus, Discoid; Neurodermatitis; Ointments; Rosacea; Tacrolimus; Tinea; Trichophyton

Lymphocyte-specific protein tyrosine kinase (Lck) plays a critical role in T cell activation. In the present study, the effect of a newly synthesized small molecule compound, 7-[2-(dimethylamino)ethoxy]-2-(4-phenoxyphenyl)-9,10-dihydro-4H- pyrazolo[5,1-b] [1,3]benzodiazepine-3-carboxamide (TKM0150) on Lck activity was investigated. TKM0150 inhibited Lck with an 1C50 value of 0.7 nM. To evaluate if TKM0150 is a specific inhibitor of Lck, the activity against several Src (Proto-oncogene tyrosine-protein kinase Src) and non-Src family kinases were assayed. TKM150 inhibited Src family kinases, Src and Csk (c-Src kinase) (with IC50 values of 0.6 nM and 1.7 nM, respectively) as well as Fyn (p59-Fyn) and Lyn (tyrosine-protein kinase Lyn) at a dose of 1 microM; however, it did not inhibit kinase which is a non-Src family kinase in the tyrosine kinase (TK) group, nor kinases in other groups. Then, the anti-inflammtory potential of TKM0150 was evaluated by known experimental models. TKM0150 inhibited the murine mixed lymphocyte reaction (MLR) in vitro with an IC50 value of 0.7 nM, and 2,4,6-trinitro-1-chlorobenzene-induced contact hypersensitivity in vivo at a dose of 0.3 and 1% w/v administered topically. These results indicate that TKM0150 is a specific inhibitor of Lck/Src kinase and can block T cell-mediated responses in vitro and in vivo. Accordingly, TKM0150 would be expected as a drug candidate for treating T cell-mediated disorders including atopic dermatitis.

Topics: Animals; Benzodiazepines; Dermatitis, Contact; Female; Immunosuppressive Agents; Indicators and Reagents; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Picryl Chloride; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Substrate Specificity; T-Lymphocytes; Tacrolimus

Tacrolimus inhibits T-lymphocyte activation and dermal Langerhans' cells, without the side-effects of corticosteroids. The safety profile of tacrolimus makes it a promising therapeutic option for dermatitis affecting the delicate periorbital skin.. To access the efficacy and tolerability of tacrolimus ointment 0.1% in the treatment of allergic contact eyelid dermatitis.. Twenty adults (16 women, 4 men) with eyelid dermatitis and with at least one positive patch test reaction to relevant contact allergens were treated with topical tacrolimus in a prospective, open-label, non-comparative clinical study. Dermatitis was graded at baseline, at day 30 and day 60, using a 4-point grading system for the following parameters: erythema, oedema, scaling, lichenification, fissuring (investigator assessment) and burning/stinging and pruritus (patient assessment).. All patients completed the study. Erythema, oedema, scaling and lichenification showed improvement from baseline to 30 days of treatment ( P < 0.001), but fissuring was not significantly affected. At 60 days, no further improvement of these investigator parameters was observed. Patient parameters improved significantly by day 30 ( P < 0.004) and there was a trend for further improvement at the end of 60 days (for burning, P = 0.046; for pruritus, P = 0.059). Ten per cent of patients mentioned burning and itching, at the application site, during the first days of treatment. No other adverse events were observed.. Topical tacrolimus is a promising alternative in patients with allergic contact eyelid dermatitis. Therapy was effective by 1 month and was well tolerated. These preliminary results merit a larger, controlled, study.

Topics: Adult; Aged; Dermatitis, Contact; Eyelid Diseases; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Tacrolimus

The topical calcineurin inhibitors pimecrolimus and tacrolimus have been demonstrated to be an effective new anti-inflammatory therapy. The only clinically relevant side-effect reported is transient application site burning and stinging itch at the beginning of topical therapy.. In order to understand the underlying mechanism of this effect, we examined whether or not the compounds are able to stimulate neuropeptide release in normal murine skin as well as in a mouse model of experimentally induced irritant contact dermatitis.. Balb/c mice were treated with 1% pimecrolimus cream or 0.1% tacrolimus ointment. Untreated and corresponding vehicle-treated mice served as controls. Skin specimens were investigated by light, immunofluorescence and electron microscopy as well as enzyme-linked immunosorbent assay and polymerase chain reaction.. Topical application of pimecrolimus and tacrolimus was followed by an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibres in murine skin during the early inflammatory response. The release of the neuropeptides and their binding to mast cells (MCs) led to MC degranulation. Mediators of MCs such as histamine and tryptase may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1, proteinase-activated receptor 2) on sensory nerve fibres, which explains the initial side-effects during therapy with calcineurin inhibitors.. It may be speculated that calcineurin inhibitors directly stimulate intracellular signalling pathways or bind to ion channels such as transient receptor potential vanilloid 1 or receptors involved in nociception.

Topics: Administration, Topical; Animals; Cell Degranulation; Dermatitis, Contact; Immunosuppressive Agents; Mast Cells; Mice; Mice, Inbred BALB C; Models, Animal; Neuropeptides; Ointments; Skin; Substance P; Tacrolimus

The induction of a granulomatous inflammation by jellyfish toxins is rare. More typically, acute toxic and urticarial reactions are seen. An 11-year-old boy developed a striated urticarial erythema on the left cheek after contact with a gelatinous mass while swimming in the sea in Croatia. After initial erosion, a striated induration developed in the area of contact. Histological examination revealed a granulomatous inflammation with some eosinophils. While topical steroid-based antiinflammatory and antibacterial therapy over several weeks was not effective, topical therapy with tacrolimus 0.1% for two two-week treatment periods led to healing of the skin changes with a slight scar. There was no clinical recurrence after 5 month of follow-up.

Topics: Animals; Bites and Stings; Child; Cnidarian Venoms; Dermatitis, Contact; Humans; Immunosuppressive Agents; Male; Scyphozoa; Tacrolimus; Treatment Outcome

Topics: Animals; Bites and Stings; Child; Cnidarian Venoms; Dermatitis, Contact; Humans; Immunosuppressive Agents; Male; Scyphozoa; Tacrolimus; Treatment Outcome

As reported previously, oral administration of the calcineurin inhibitors (CNI) pimecrolimus and tacrolimus resulted in equipotent inhibition of the elicitation phase of contact hypersensitivity (CHS) in mice. The sensitization phase was inhibited by tacrolimus but was unaffected by pimecrolimus, even at higher doses.. The kinetics of lymph node hyperplasia and up-regulation of T and B cell activation antigens were analyzed to obtain a better understanding of the divergent CNI profile in CHS.. Lymph node (LN) cells of CNI-untreated and treated mice were examined with flow cytometry at various time points after sensitization with oxazolone. LN hyperplasia and drug levels were also determined.. Sensitization induced a higher portion of LN cells expressing the activation antigens CD25, CD69 and CD134 and an increase in activated B cells (B220(+)/CD40(+)) compared to naïve mice. Up-regulation of these markers was completely or profoundly blocked with tacrolimus, whereas pimecrolimus at the three-fold higher dose caused significantly less inhibition. Tacrolimus also completely blocked the sensitization-associated increase of CD11c(+) antigen presenting cells (APC) in LN, whereas pimecrolimus showed significantly less inhibition. In contrast to tacrolimus, LN weight and cellularity were not affected by pimecrolimus at any time point after sensitization. Concentration of tacrolimus in blood and in the draining LN substantially exceeded that of pimecrolimus by factors 6.7-14 and 5.6-5.8, respectively, at the same dose levels.. In contrast to tacrolimus, systemic treatment of mice with pimecrolimus only weakly interferes with lymphocyte activation and does not affect hyperplasia of the draining lymph nodes during sensitization.

Topics: Animals; CD11c Antigen; Dermatitis, Contact; Flow Cytometry; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Activation; Mice; Tacrolimus

Topics: Administration, Topical; Aged; Anti-Infective Agents; Dermatitis, Contact; Dermatologic Agents; Female; Humans; Propolis; Tacrolimus; Vulvar Diseases

Topics: Case-Control Studies; Catechols; Dermatitis, Allergic Contact; Dermatitis, Contact; Dermatitis, Irritant; Dermatitis, Toxicodendron; Humans; Immunosuppressive Agents; Ointments; Pilot Projects; Single-Blind Method; Sodium Dodecyl Sulfate; Surface-Active Agents; Tacrolimus; Toxicodendron

T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Cell Division; Cytokines; Dermatitis, Contact; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Evaluation, Preclinical; Female; Guinea Pigs; Humans; Lactams; Male; Mice; Rats; Swine; Tacrolimus; Th1 Cells; Th2 Cells

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

Recently, it has been shown that the immunosuppressive macrolide lactone, FK506, exerts good therapeutic efficacy in inflammatory skin diseases. The aim of this study was to analyze the influence of topical FK506 on molecular (IL-1alpha, IL-1beta, IL-2, IL-4, IL-12 p35, IL-12 p40, macrophage inflammatory protein-2 (MIP-2), granulocyte-macrophage CSF (GM-CSF), TNF-alpha, and IFN-gamma) and cellular (I-A+/CD80+, I-A+/CD54+, I-A+/CD69+, I-A+/B220+, and CD4+/CD25+) events in epidermal (EC) and local draining lymph node (LNC) cells during primary contact hypersensitivity responses. Cytokine mRNA levels for IL-1alpha, IL-1beta, GM-CSF, TNF-alpha, MIP-2, and IFN-gamma in EC and for IL-2, IL-4, IL-12 p35, IL-12 p40, and IFN-gamma in LNC were increased and resulted in significant LNC proliferation during oxazolone-induced contact hypersensitivity. Topical FK506 treatment dose-dependently suppressed oxazolone-induced LNC proliferation. This effect was correlated with decreased IL-1alpha, IL-1beta, GM-CSF, TNF-alpha, MIP-2, and IFN-gamma mRNA expression within the epidermis and decreased IL-12 p35 and p40 mRNA expression in LNC. Further analysis of the LNC cytokine pattern revealed that the production of both Thl (IFN-gamma and IL-2) and Th2 (IL-4) cytokines was dramatically impaired after topical FK506 treatment. Flow cytometric analysis showed that topical FK506 decreased the population of epidermis-infiltrating CD4+ T cells and suppressed the expression of CD54 and CD80 on I-A+ EC and LNC during hapten-induced contact hypersensitivity. Furthermore, topical FK506 profoundly impaired oxazolone-induced up-regulation of CD25 expression on CD4+ LNC and dramatically decreased hapten-induced expansion of I-A+/B220+ and I-A+/CD69+ LNC subsets. In conclusion, these results give new insights into the mechanisms of action of topical FK506 treatment.

Topics: Administration, Topical; Animals; Antigens, CD; B-Lymphocytes; Cell Movement; Chemokine CXCL2; Cytokines; Dermatitis, Contact; Epidermal Cells; Epidermis; Female; Histocompatibility Antigens Class II; Immunosuppressive Agents; Interferon-gamma; Interleukin-1; Interleukin-12; Lymph Nodes; Lymphocyte Activation; Mice; Monokines; RNA, Messenger; Tacrolimus; Th1 Cells; Th2 Cells; Time Factors

Topical glucocorticosteroids represent the mainstay of antiinflammatory therapy in the treatment of inflammatory skin diseases. Their clinical use, however, is limited by local and systemic side-effects. Thus, in dermatopharmacology there is a large demand for alternative non-steroidal antiinflammatories. Other than transplantation models, most of the frequently used in vivo test systems for assessment of drug-induced immunosuppression measure changes in inflammatory skin responses by means of skin erythema and edema after challenge of sensitized animals. The aim of this study was to develop an alternative mouse model to detect and analyse immunosuppressive effects of topically applied drugs. On the basis of a modified local lymph node assay, we analysed effects of topical hydrocortisone, dexamethasone, mometasone furoate and FK506 (tacrolimus) during the induction phase of contact hypersensitivity. On 4 consecutive days, NMRI mice were treated on the dorsal surfaces of both ears with increasing concentrations of test compound. During the last 3 days, the mice received in addition the contact sensitizer, oxazolone (1%). On day 5, draining auricular lymph nodes were removed in order to assess lymph node cell counts and perform flow cytometric analysis of lymph node cell subpopulations (CD4+/CD25+, Ia+/CD69+, Ia+/B220+). All test compounds proved to exert significant immunosuppressive effects after topical application, but showed differences in their immunomodulatory potential. In conclusion, the local lymph node assay serves as an appropriate model to characterize immunosuppressive effects of topically applied drugs by measuring immunologically relevant end-points.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Dermatitis, Contact; Dexamethasone; Drug Evaluation, Preclinical; Female; Hydrocortisone; Immunosuppressive Agents; Lymph Nodes; Mice; Mometasone Furoate; Oxazolone; Pregnadienediols; Tacrolimus

Five repeated topical applications of 2,4-dinitrofluorobenzene to the ears of BALB/c mice resulted in contact dermatitis on the ears as well as significant elevation in dinitrophenol-specific IgE antibody and total IgE in the serum. FK-506 and cyclosporin A inhibited the development of contact dermatitis in terms of skin thickness and histopathological changes of skin lesions. On the contrary, these two drugs potentiated dinitrophenol-specific and total IgE antibody production without affecting IgG and IgM levels in serum. The expression of interferon-gamma mRNA in reverse transcriptase-polymerase chain reaction in the ear was inhibited by FK-506 and cyclosporin A. The expression of interleukin-4 mRNA, germline C epsilon and productive C epsilon in the auricular lymph node was not affected by these two drugs. Contrary to the above in vivo findings, the immunosuppressors, FK-506 and cyclosporin A, inhibited the production of interferon-gamma and interleukin-2 by cultured Th1 cells (1E10.H2 cells) and of interleukin-4 and -5 by Th2 cells (D10.G4.1 cells) in vitro. These results indicated that FK-506 and cyclosporin A selectively inhibited the Th1 cell-mediated contact dermatitis and potentiated the Th2 cell-mediated IgE antibody production in vivo. This potentiation is probably due to the down-regulation of interferon-gamma production by Th1 cells after the treatment with these drugs. However, because FK-506 and cyclosporin A inhibited the production of cytokines by both Th1 and Th2 cells in vitro and these two immunosuppressors showed higher selectivity toward inhibiting Th1 cell-mediated reactions by limitations in vivo experiments.

Topics: Animals; Cyclosporine; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Female; Haptens; Immunoglobulin E; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Tacrolimus; Th1 Cells

Topics: Animals; Dermatitis, Contact; Dinitrochlorobenzene; Disease Models, Animal; Guinea Pigs; Humans; Immunoassay; Immunosuppressive Agents; Lymph Nodes; Male; Oxazolone; Tacrolimus

Azelastine hydrochloride (AZE) is an anti-allergic drug that inhibits the release of various chemical mediators from mast cells. We compared the immunosuppressive effects of AZE and FK-506 in vivo and in vitro. Topical application of AZE strongly inhibited the efferent phase of contact hypersensitivity, as did application of FK-506. In in vitro experiments, we found that 1) the suppression by AZE on interleukin (IL)-2 production from splenic T cells was partial and considerably large amounts of IL-2 were still produced, even in the presence of 10(-5) M of AZE, which was in sharp contrast to the observed marked inhibition of [3H]-TdR incorporation; 2) AZE significantly inhibited the phorbol myristate acetate-induced IL-2 responsiveness; 3) AZE did not inhibit the IL-2 receptor alpha expression of activated T cells; and 4) the significant inhibitory action was still observed even when AZE was added at 48 h after the initiation of culture. In regard to FK-506, we found that 1) FK-506 completely blocked the production of IL-2; 2) exogeneous IL-2 consistently restored the FK-506-induced inhibition; 3) FK-506 affected the phorbol myristate acetate-induced IL-2 responsiveness very little, if any; and 4) the significant suppression was observed only when FK-506 was added within 24 h after the initiation of culture. Thus, AZE exerts its in vitro immunosuppressive activity preferentially by interfering with the IL-2 responsiveness, with partial inhibition of IL-2 production. Conversely, FK-506 acts as a strong inhibitor of IL-2 production without a prominent effect on IL-2 responsiveness. The immunosuppressive activity of AZE shown in vitro may also be operative in vivo and may be applicable for topical use.

Topics: Administration, Topical; Animals; Bronchodilator Agents; Cell Division; Cells, Cultured; Dermatitis, Contact; DNA; Immunosuppressive Agents; In Vitro Techniques; Interleukin-2; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Phthalazines; Receptors, Interleukin-2; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate; Thymidine; Time Factors; Tritium

The effect of FK506, a potent immunosuppressive agent, on 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13- acetate (TPA)-promoted skin papilloma formation was examined in CD-1 mice. A topical application of FK506 to mouse skin 15 min before each TPA treatment resulted in a dose-related inhibition of tumor formation. FK506 (1 mumol) almost completely inhibited tumor formation. This inhibitory effect of FK506 was not due to any damage inflicted on the initiated cells but due to its anti-tumor-promoting action. A topical application of FK506 also inhibited epidermal ornithine decarboxylase induction and skin inflammation caused by TPA in a dose-related manner. Significant inhibition by FK506 of TPA-induced endogenous protein phosphorylation in intact epidermal cells was not detected. These results indicate that FK506 inhibits TPA-induced tumor promotion at a step distal to the endogenous protein phosphorylation by TPA.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Dermatitis, Contact; Enzyme Induction; Female; Mice; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Papilloma; Phosphorylation; Skin Neoplasms; Tacrolimus; Tetradecanoylphorbol Acetate

A 30% burn injury was found highly immunosuppressive in mice by means of two in vivo measurements of cell-mediated immunity, and this immunosuppression could be prevented by early excision and grafting. FK506, a new immunosuppressive agent, was given at different doses for 12 days after early excision and grafting following burn and all doses prolonged the acceptance time of allografts from 14 to 20 days. Allograft rejection was not seen when animals were on the drug. Higher doses prolonged the rejection more, even after the cessation of the drug, and they caused some degree of immunodepression. Immunosuppressive treatment with FK506 when used following burn injury affected cell-mediated immunity minimally to moderately when compared to burned control groups.

Topics: Animals; Burns; Dermatitis, Contact; Disease Models, Animal; Female; Graft Survival; Immunity, Cellular; Lymph Nodes; Mice; Mice, Inbred BALB C; Skin Transplantation; 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

Topics: Administration, Topical; Dermatitis, Contact; Humans; Tacrolimus