Structure-activity relationships in allergic contact dermatitis

Primin (2-methoxy-6-pentyl-1,4-benzoquinone)is a naturally-occurring strong sensitizer from Primula obconica (Primulaceae), To determine the effect of side-chain length on senstizing potency 15 analogues with linear side chains from to from C₁, to C₁₅ and 4 C₆- analogues with branched side chains were prepared synthetically and devoted to experimental sensitization in guinea pigs The results showed an increase of the sensitizing capacity with increasing length of the alkyl side chain from C₁ to C₁₀, reaching a maximum at C₁₁ and C₁₂. On further elongation the senstizing potency decreased beyond C₁₃ reaching values which finally were as low as those of the C₁ and C₃ derivatives. The results mirror finding which finally were as low as those of the C₁ and C₃ derivatives. The results mirror findings which formerly have been obtained with other non-quinonoid compounds like catechols, phenols hydroquinones and gallates. In the plant kingdom. Compound approximating an "ideal allergen" consisting of a quinonoid ring with a 10 or 11 carbon-remarkably strong sensitizer found in Wigandia caracasana (Hydrophyllaceae)     

Different physical forms of maleopimaric acid give different allergic responses

Endo-maleopimaric acid (MPA) is a contact allergen formed when colophonium is "modified" with maleic anhydride or fumaric acid. Previous patch testing showed a higher allergic response to petrolatum (pet.) preparations of MPA in amorphous form compared to MPA in crystalline form. In the present study, the impact of the physical form of MPA on the allergic response was investigated. Since the amorphous form is difficult to standardize, crystalline MPA mechanically incorporated or dissolved in pet. was used. A lower eliciting capacity was obtained from crystalline MPA, compared to that obtained from dissolved MPA, in guinea pigs intradermally induced with MPA. Using 3H-MPA a 3X difference in the dissolution into synthetic sweat from MPA dissolved in pet., compared to MPA mechanically incorporated, was demonstrated. A difference in bio-availability between dissolved and crystalline MPA could therefore be assumed. Crystalline MPA had a low sensitizing capacity compared to that seen for amorphous MPA in previous studies. The amorphous form of MPA is likely to have a larger surface area than crystalline MPA, with less ordered molecules, resulting in a higher dissolution rate and a greater bio-availability. Modified colophonium exists as amorphous solids and as viscous liquids. Thus, exposure will probably be to non-crystalline MPA and cases of contact allergy could be overlooked when screening with crystalline MPA.     

Topical cyclosporine: effects on allergic contact dermatitis in guinea pigs

Cyclosporine (CSA) is an effective immunosuppressive agent and is used in tissue transplantation. The present investigation was undertaken to determine the effect of topical delivery of CSA on allergic contact dermatitis in guinea pigs. Topical 15% CSA in an azone (1-dodecylazacycloheptan-2-one)-containing vehicle blocked local elicitation in previously dinitrochlorobenzene (DNCB) sensitized animals that received a single topical application just prior to elicitation. Elicitation was not blocked at a distant site, indicating a local effect of topical CSA. In contrast, topical CSA when applied twice daily for a total of 5 applications during sensitization only, did not block subsequent elicitation. These experiments suggest that cyclosporine may be beneficial in the therapy of human contact dermatitis, as well as other T cell mediated dermatoses.     

Influence of the vehicle on elicitation of contact allergic reactions to acrylic compounds in the guinea pig

Many factors can influence the elicitation of hypersensitivity reactions in guinea pigs and humans. The effect which the vehicle might have on the test response in guinea pigs sensitized with various acrylic compounds, using the "guinea pig maximization test", has been investigated. A marked decrease in the number of positive animals was seen when acetone was used as test vehicle, compared to petrolatum. The same result was seen with alcohol as vehicle, when neopentyl glycol diacrylate (NPGDA) was used as an acrylic monomer model. The patch test locations on the guinea pig flank, also affected the test response. Half of the animals did not react when challenged near the abdomen, compared to a test site near the back. By means of HPLC-analysis, the possible adsorption of the acrylic monomer to the aluminium chamber or filter paper disc, was analysed. Our findings did not indicate that adsorption occurs. A decrease in the amount of acrylic monomer in the chamber with increasing time, was noted. There was a marked difference in the monomer residue between solutions with (darkness) and without (daylight) inhibitor. The monomer decrease was also more affected by an aluminium surface than a glass or filter paper surface. Aluminium oxide probably enhances the polymerization process. The discrepancy between the test results in this study, when petrolatum and acetone were used as test vehicles, is due to a polymerization process of the acrylic compounds. Thus, the petrolatum vehicle probably prevents polymerization of the acrylic monomer.     

UVB serum factor: suppression of allergic contact dermatitis in guinea pigs

Serum from guinea pigs exposed to a single high dose of UVB and from controls was injected into the spleen of normal animals 5 days prior to sensitization. When 1.0 ml was transferred 4.5 h after irradiation, immunosuppression was obtained. Transfer of 1.5 ml of serum 2.5 h after irradiation failed to induce immunosuppression. This experimental model in guinea pigs might be valuable in further studies investigating the effect of other modalities of ultraviolet exposure (e.g., PUVA or high-dose UVA) on the release of soluble serum factor(s) inducing immunosuppression in allergic contact dermatitis.     

Nickel allergy: tolerance to metallic surface-plated samples in nickel-sensitive humans and guinea pigs

The purpose of this work is to evaluate in nickel-sensitive patients and guinea pigs the tolerance to nickel samples, surface-plated with one or several metals of varying structures and thicknesses. All the metal samples elicited allergic reactions in the guinea pig. In humans, absolute tolerance was not observed for any sample. In humans, the interposing of a layer of bright copper between nickel and surface chrome greatly increased the tolerance.     

Topical application of artesunate on guinea pig allergic contact dermatitis

Artesunate is derived from the Chinese medicinal herb qinghao. Many animal studies suggest that systemic artesunate has immunoregulatory activity. We investigated the effect of topical artesunate on contact sensitivity in guinea pigs sensitized with DNCB. Female hairless guinea pigs were used and the contact reaction graded by visual (5 point) score and erythema measured with a color analyzer. Topical artesunate inhibited the elicitation reaction of contact hypersensitivity when given at the 1st and 12th h after challenge ( p < 0.05), but showed no effect when given from day 3 to day I before challenge ( p > 0.05). Artesunate had no effect on toxic (irritant) contact dermatitis from 20% croton oil ( p > 0.05). The results indicate that topical application of artesunate may offer a novel treatment of allergic contact dermatitis and other cutaneous immune-mediated disorders.     

A quantitative structure activity/dose response relationship for contact allergic potential of alkyl group transfer agents

As part of the investigation of structure activity relationships in contact allergy, it has been shown that methyl transfer agents are capable of acting as skin sensitizers. This work has now been extended to a more general examination of alkyl transfer reactions. The modified single injection adjuvant test has been used to investigate the sensitization potential of C12, C16 and unsaturated C18 alkyl transfer agents. Dose responses to challenge and the patterns of cross-reactivity between these materials and methyl transfer agents have been studied. All alkyl transfer agents examined were potent sensitizers in the guinea pig. There was evidence of mutual cross-reactivity between all alkyl transfer agents examined (including methyl transfer agents). Analysis of the data in terms of a modified relative alkylation index showed evidence of an overload effect. The sensitization data has been accurately modelled using a mathematical equation. These results emphasize the possibilities for relating physicochemical parameters and skin sensitization potential. Further studies with alkyl transfer agents are in progress of amplify the observations and conclusions presented in this report. No in vitro model is available for the prediction of skin sensitization potential. Therefore an approach based on a model using physicochemical criteria is the most likely route to a reduced requirement for animal testing.     

Experimental contact sensitization with 3,4,5-trichloropyridazine

The potential of 3,4,5-trichloropyridazine to induce contact sensitization was assessed in the guinea pig maximization test of Magnusson and Kligman and also in the closed patch test described by Buehler. The test material was a 1% solution of 3,4,5-trichloropyridazine in a highly refined mineral oil. The test material elicited moderate to severe irritation when diluted in mineral oil to concentrations of 15-25% and minimal irritation at concentrations of 1-3%. Both tests clearly indicated that 3,4,5-trichloropyridazine was a contact sensitizer to guinea pigs, although the response was stronger in the maximization test. Sensitization was distinguished from irritation by the use of concurrent irritation control groups.     

Regulation of nickel-induced T-cell responsiveness by CD4+CD25+ cells in contact allergic patients and healthy individuals

In this study, we investigated the capacity of CD4⁺CD25⁺ regulatory T cells to suppress nickel‐specific effector T cells, both in nickel‐allergic patients and healthy controls. CD4⁺ cells isolated from allergic patients showed an increased proliferative response to nickel, whereas CD4⁺ cells from negative controls did not respond to allergen. When CD4⁺CD25⁺ cells were depleted, nickel‐specific responsiveness was strongly increased both in allergic and in non‐allergic individuals, with the most pronounced effect in allergic patients. These regulatory T cells were anergic to nickel but inhibited nickel‐specific CD4⁺CD25^– effector T cells in coculture experiments. CD4⁺CD25⁺ cells from nickel‐allergic patients showed only a limited capacity to suppress effector T‐cell responsiveness, because an increased nickel reactivity could still be detected in these cocultures. None of the isolated CD4⁺CD25⁺ cells, either isolated from healthy controls or allergic patients, produced IL‐10 in response to nickel. Overall, these results support the view that CD4⁺CD25⁺ cells can control the activation of nickel‐specific effector T cells in non‐allergic individuals, whereas this regulatory capacity is impaired in allergic patients. To investigate the presence of allergen‐specific regulatory T cells in truly naïve, non‐sensitized individuals, T‐cell reactivity should also be studied with non‐environmental contact allergens, such as para‐phenylenediamine.     

Comparison of methods for the macroscopic assessment of epicutaneous allergic contact reactions in guinea pigs

40 guinea pigs were sensitised with a 50% solution of 2,4-dinitro-1-chlorobenzene (DNCB) and challenged 14 days later with DNCB 0.05%. Four parameters were determined to evaluate the challenge reaction after 24, 48, 72 and 96 h: (a) intensity of erythema, (b) reaction area (product of the largest diameters of the reaction in vertical alignment), (c) increase in skinfold thickness and (d) reaction volume (product of the reaction area and the increase in skinfold thickness). The test reactions were read blind by 2 independent observers, yielding small but significant differences in all methods except determination of the reaction area. Further statistical analysis revealed a linear correlation between the intensity of erythema and the other 3 parameters determined, as well as between the reaction area and the reaction volume. In contrast, the increase in skinfold thickness did not correlate linearly either with the reaction area or the reaction volume. When the results of the 24- and 48-h readings were compared, the characteristic crescendo reaction of contact allergy was demonstrable by all methods except the determination of the reaction area. After the 48-h reading, a continuous decrease of reactions was found with all methods. It is concluded that the determination of the reaction area and consequently of the reaction volume are not suitable for exact measurement of epicutaneous allergic contact reactions in guinea pigs. The most precise results will be obtained by measuring the increase in skinfold thickness, whereas the determination of the intensity of erythema, which is easier to perform, may be sufficient for many purposes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the allergenicity of Baltic amber

Baltic amber is a fossil resin deposited 36-7 million years ago and one source may be the extinct tree Pinites (Pinus) succinifer. Palaeobotanical studies of amber have an extensive literature, but the aspect of allergenicity has not been addressed before. The aim of our study was to present the results from sensitization studies with Baltic amber and to discuss these in view of possible cross-reactivity with contact allergens in colophony. It is concluded that allergens found in colophony can also be present in Baltic amber. The main resin acids were identified in an ether-soluble extract of amber. Amber suspended in petrolatum caused positive patch test reactions in patients with contact allergy to colophony. Furthermore, animals sensitized to colophony showed positive reactions to amber, but animals induced with amber did not react when challenged with amber. A use test with an amber necklace in patients with positive test reactions to amber and colophony was negative, which supports the view that amber in personal ornaments is not a clinical problem.     

Effect of vehicle on elicitation of DNCB contact allergy in the guinea pig

22 DNCB sensitized guinea pigs were challenged with varying amounts dissolved in alcohol, acetone and olive oil. DNCB applied in alcohol resulted in almost 100% positive reactions; the test scores correlated to dose. When similar amounts were applied in alcohol and acetone, the former produced a significantly higher degree of positivity. The importance of defining allergen concentration, volume or weight of test substance applied and test are size, when comparing test results in guinea pigs and humans, is emphasized.