Jean-Luc Stampf

Allergic contact dermatitis due to sesquiterpene lactones

Several compounds containing the α‐methylene‐γ‐butyrolactone moiety have been tested on human volunteers and on guinea‐pigs; the animals were experimentally sensitized by alantolactone, iso‐alantolactone and laurel oil. Of the two new lactones, spirolactone was the more reactive: this was confirmed by both animal and human testing. The synthetic lactones are less reactive than natural ones. α‐Methylene‐γ‐butyrolactone itself does not elicit cross‐reactions in guinea‐pigs sensitive either to alantolactone or to isoalantolactone, or in patients sensitive to sesquiterpene lactones. The α‐methylene‐γ‐butyrolactone group is necessary for cross‐reaction, but to be active, it has first to be substituted. It was also found that isoalantolactone, allegedly not allergenic, is in fact a sensitizer and cross‐reacts with alantolactone. The cross‐reaction between laurel and Frullania, found in man, also occurs in guinea‐pigs. It is more evident when sesquiterpene lactone is the sensitizer and laurel used to elicit reaction.

ATPase and morphologic changes in Langerhans cells induced by epicutaneous application of a sensitizing dose of DNFB

We have previously described an ATPase Langerhans cell (LC) staining technique allowing progression from light to electron microscope observation. Using this technique we have studied, following epicutaneous application of a sensitizing dose of a hapten, 2,4-dinitro-1-fluorobenzene (DNFB), the fate of the epidermal LC located in the sensitization zone. We wanted to know, under the light microscope, if the density and/or morphology of the LC are modified by such a treatment and, under the electron microscope, what are the ultrastructural changes accompanying the possible light microscope modifications. Under the light microscope, the observation of LC during the 5 d necessary for the development of contact sensitivity to DNFB shows that their number drops in the course of the first 24 h to normalize again 3 d later. Under the electron microscope, observations over the first 24 h revealed that LC remained in the epidermis, but were ATPase-negative. The disappearance of the membrane ATPase activity took place while the LC presented an increased number of coated pits, coated vesicles, endosomes, and lysosome organelles which characterize, at the ultrastructural level, the process of receptor-mediated endocytosis (RME). Following RME, many Birbeck granules (BG) appeared in the cytoplasm. Thus, epicutaneous application of DNFB leads to an endocytic activation of LC. However, the ligand(s) and/or the cell-surface components, which probably internalize during the RME process, remain unknown.

Enantiospecificity in allergic contact dermatitis A review and new results in Frullania‐sensitive patients

Allergic contact dermatitis is essentially enantiospceific: sensitization to one enantiomer generally does not imply elicitation to the mirror‐image allergens. Examples from patients allergic to Frullania. and from the literature (usnic acids. 4‐methoxydalbergioes, γ‐methyl‐α‐methylene‐γ‐butyrolactones, frullanolides) are discussed.

The sensitizing capacity of helenin and of two of its main constituents, the sesquiterpene lactones alantolactone and isoalantolactone: a comparison of epicutaneous and intradermal sensitizing methods in different strains of guinea pig

The sensitizing capacities of helenin (an extract from a Compositae Inula helenium L.), alantolactone and isoalantolactone (two isomeric sesquiterpene lactones), were assessed by sensitizing guinea pigs of different strains: albino Himalayan spotted, Pirbright and Hartley. Both alantolactone and isoalantolactone are found to be sensitizers if injected intradermally. Only Pirbright guinea pigs showed a high sensitization rate by the open epicutaneous technique; with this method, alantolactone was the more potent sertsitizer.

Allergic contact dermatitis to α-methylene-γ-butyrolactones: Preparation of alantolactone-protein conjugates and induction of contact sensitivity in the guinea pig by an alantolactone-skin protein conjugate

Abstract Sesquiterpene lactones have been implicated as causative agents of allergic contact dermatitis to plants of the Compositae family. It has been postulated that these compounds undergo nucleophilic addition through their α-methylene-γ-butyrolactone conjugated system and that this mechanism accounts for their covalent attachment to carrier molecule(s). The present report presents evidence of covalent bond formation between alantolactone, a typical sesquiterpene lactone, and model proteins. Evidence of alantolactone-ribonuclease A adduct formation has been obtained from release of alantolactone under thermal treatment of the adduct in a gas Chromatograph and in a mass spectrometer and from comparative fingerprint analysis. We also report that alantolactone rapidly inhibits the enzymic activity of aspartate β-semialdehyde dehydrogenase, by reaction with a cysteinyl residue of the enzyme. An adduct of alantolactone-guinea pig skin proteins induces, in guinea pigs, a state of delayed hypersensitivity to alantolactone and cross-reaction to other natural or synthetic α-methylene-γ-butyrolactones, as assessed by epicutaneous tests to the haptens.

Allergic contact dermatitis to tulips: An example of enantiospecificity

SummaryAllergic contact dermatitis (ACD), an immunological reaction of the skin resulting from contact with reactive compounds occurring in plants was shown to the enantiospecific (animals sensitized to a compound do not react to its nonsuperimposable mirror image). Thus, when guinea pigs were experimentally sensitized to (+)-tulipalin B (a compound present in tulip bulbs) they did not react to its enantiomer, (-)-tulipalin B. This was also true for (+)- and (-)-β-hydroxy-γ-methyl-α-methylene-γ-butyrolactones.

Synthesis of BOC-CYS-ALA-OME and its stereoselective addition to α-methylene-γ-butyrolactones

The stereoselective addition of enantiomerically pure (as shown by 200 MHz 1H NMR study) dipeptide Boc-Cys-Ala-OMe 4 to α-methylene-γ-butyrolactones has been studied. The stereoselectivity of the addition parallels the enantioselectivity observed in the allergic contact dermatitis induced in guinea pigs.

Cross-reaction in allergic contact dermatitis from α-methylene-γ-butyrolactones: importance of the cis or trans ring junction

Cross‐reaction in allergic contact dermatitis (ACD) is a highly stereoselective process. The importance of the cis or trans ring junction in α‐methylene‐γ‐butyrolactones in cross‐reactivity was investigates by reacting Helenin® (mostly a mixture of natural allergenic sesquiterpene lactones alantolactone 1 and isoalantolactone 2, which present a cis ring junction) in guinea pigs sensitized to model allergenic α‐methylene‐γ‐butyolactones: cis‐bicyclin lactone 3 and trans‐bicycle lactone 4.

Allergic contact dermatitis to methylenelactones use of lymphocyte transformation test

SummarySeventeen guinea pigs were sensitized to alantolactone, a natural sesquiterpene lactone known for its sensitizing properties, using intradermal injections in Freunds complete adjuvant. Guinea pig skin protein extracts (SPE) were used to make conjugates with alantolactone and an isomer, isoalantolactone. Lymphocyte blastogenesis was observed with SPE-alantolactone conjugates, as well as with guinea pig albumin-lactone conjugates. In six cases, stimulation was noted with unconjugated haptens. These results do not show a high degree of hapten-carrier specificity in contact sensitivity to alantolactone, induced by unconjugated hapten injections. Cross-sensitivity with SPE-isoalantolactone conjugate was also observed.

Stereochemistry of the michael addition of lysine derivatives to α-methylene-γ-butyrolactones

Abstract The stereochemistry of Michael additions of Boc-protected lysine derivatives ( N -Boc-lysine-OMe and N -Boc-lysinyl-alanine-OMe) to natural sesquiterpene α-methylene-γ-butyrolactones has been investigated.