Late-phase Skin Reactions Research Articles

The relationship between infiltrating CD4+ lymphocytes, activated eosinophils, and the magnitude of the allergen-induced late phase cutaneous reaction in man.

Abstract The phenotype and activation status of leukocytes infiltrating human late phase allergic skin reactions were investigated by immunocytochemistry using a panel of mAb. Late phase skin reactions were induced in atopic individuals by intradermal challenge with allergen extract (grass pollen or house dust mite) and skin biopsies were obtained 6, 24, or 48 h after challenge. Cryostat sections were examined for evidence of infiltration and activation of T cells and eosinophils. Biopsies from saline-challenged control sites were used for comparison. A substantial number of CD3+ cells were observed close to the dermal capillaries. The number of CD4+ cells showed a similar pattern but few CD8+ cells were seen. The ratio of CD4 and CD8 subsets in tissue did not relate to the CD4/CD8 ratio in the peripheral blood. Two observations suggested that T cells had become activated: first, a small number of infiltrating cells bore receptors for IL-2, and second, there was indirect evidence of IFN-gamma secretion, demonstrated by increased expression of HLA-DR on endothelial cells and de novo expression of CD4 Ag on epidermal Langerhans cells. Activated eosinophils were detected in most of the allergen-challenged biopsies. The late phase reaction diameter at 6 h correlated with the number of activated eosinophils at 48 h (r = 0.61, p = 0.05), but not with infiltration by T cells. There was a strong correlation between the numbers of CD4+ cells and activated eosinophils at 24 h (r = 0.94, p less than 0.001). These findings suggest that interactions between T lymphocytes and eosinophils in reactions to airborne allergens may be more important than has previously been recognized.

Immediate and late phase allergic cutaneous reactions are not inducers of unspecific or specific local hyperreactivity.

The present study evaluates the possibility of allergen-induced unspecific and specific dermal hyperreactivity with special reference to the presence of late cutaneous reactions and allergen-induced nasal hyperreactivity. Twenty-six patients with strictly seasonal allergic rhinitis participated. All had a positive skin prick test for birch (Betula verrucosa) and/or timothy (Phleum pratense). Ten patients had previously displayed an allergen-induced nasal hyperreactivity and six patients a late cutaneous reaction. An initial skin prick test with a relevant pollen allergen was done in triplicate. The immediate skin reactions were recorded after 15 min and any late-phase reaction after 6 h. Twenty-four hours later the patients were retested. The same pollen allergen was sited in the first flare reaction from the previous day. A histamine prick test was sited in the weal as well as in the third reaction from day 1. A histamine control was also performed in a previously unaffected area. The allergen-induced weal reactions decreased significantly at rechallenge compared with the results from the previous day (P less than 0.05). The histamine tests resulted in similar skin reactions regardless of whether or not they were done on a previous allergen test site. This was true for both specific and unspecific reactions when the subgroups of patients with previously demonstrated allergen-induced nasal hyperreactivity or late-phase skin reactions were evaluated separately. These results indicate that allergen-induced hyperreactivity is not a general feature of allergic inflammation but is a phenomenon restricted to specific sites, such as the airway mucosa.

The pattern of human late-phase skin reactions to extracts of aeroallergens

The kinetics and dose response of cutaneous late phase reactions (LPR) (defined as >5 mm induration 6 hours after intradermal challenge with allergen) were studied in 20 randomly selected subjects with atopic rhinitis. When subjects were challenged intradermally with 0.2 biologic unit (BU) of Dermatophagoides pteronyssinus or grass pollen, wheal-and-flare reactions were elicited without subsequent LPRs. With 30 BU, all subjects developed LPRs, whereas 1 and 10 BU provoked LPRs in 28% and 64%, respectively. No biphasic responses were detected. At all concentrations which progressed to form an LPR, a palpable skin reaction was continuously present and either remained constant or increased steadily in magnitude during 6 hours. Skin reactions of similar diameter provoked by histamine resolved fully within 2 hours. Thus, we confirm that the development of a macroscopic cutaneous LPR requires a higher concentration of allergen than the wheal-and-flare reaction. Together with our other findings, these results suggest that all untreated atopic individuals are capable of mounting an LPR if they are challenged with sufficient allergen. In contrast to the asthmatic response to inhaled allergen, the cutaneous wheal and LPR are not biphasic.

530 T lymphocyte subsets in human late-phase skin reactions

530 T lymphocyte subsets in human late-phase skin reactions

Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids

The effect of prolonged topical dermal glucocorticosteroid treatment on the immediate and late-phase allergic skin reaction was studied in a double-blind, randomized, placebo-controlled study. Seventeen patients with hay fever and with a positive skin test for timothy and/or birch pollen allergens were studied in a pollen-free season. Skin prick tests for these two allergens as well as a negative saline and a positive histamine control were made with a preloaded standardized prick test needle. The area of the induced wheal-and-flare reaction was measured 15 minutes after allergen application, and any induced late-phase responses were measured after 6 hours. After a baseline recording, the patients treated the volar aspect of one forearm twice daily with a cream of 0.05% clobetasol 17-propionate and the other forearm with the equivalent vehicle in a randomized, double-blind fashion. After 1 week the skin prick test was repeated on both arms. A statistically significant reduction of the allergen-induced wheal-and-flare response was found after active treatment as compared to control and pretreatment values. A reduction was also found in the histamine-induced flare but not the wheal reaction as compared to the control. A late-phase dermal reaction was found in six of the patients, and this was statistically significantly reduced by the glucocorticosteroid pretreatment. Thus, in similarity to findings in vivo on the human nose and bronchus, we found, in addition to the well-known glucocorticosteroid-induced reduction of the allergic late-phase response, an inhibition of the dermal immediate allergic reaction as well. The prerequisite for demonstrating any effect on the immediate allergic reaction by glucocorticosteroids appears to be topical application for a prolonged time before allergen exposure. As dermally applied glucocorticosteroids are commonly used for a variety of disorders, the interference of this treatment with the skin test producing a false negative result must be kept in mind.

Suppression of late-phase skin reactions by immunotherapy with ragweed extract

The cutaneous late-phase reaction (LPR) to ragweed was studied in untreated ragweed-allergic individuals and patients receiving 3 to 5 years of immunotherapy demonstrating clinical improvement. The magnitude of immediate skin reactions and the initial levels of the specific IgE and IgG antiragweed antibodies were similar in both groups. The LPR was elicited by administering a skin test with ragweed extract at 10 times the concentration required to elicit a 4 + immediate reaction and appeared as an erythematous-edematous lesion associated with pruritus. In the untreated group 94% developed an LPR (59 ± 32 mm at 4 hours and 67 ± 30 mm at 8 hours) at this dose. In the treated group only one third developed an LPR, one third had partial response measurable at one of these two times, and one third failed to develop any LPR (21 ± 20 mm at 4 hours, p < 0.002, and 20 ± 22 mm at 8 hours, p < 0.001). Therapy resulted in a twentyfold increase of IgG antiragweed level and in a decline of IgE antiragweed. The size of the LPR correlated inversely with the level of IgG antiragweed ( p < 0.01; r = −0.52) but not with IgE antibody. Thus, in a retrospective analysis immunotherapy was associated with the suppression of the skin LPR, and the magnitude of the LPR was correlated with the level of IgG antiragweed. We suggest that the clinical efficacy of immunotherapy is related in part to effects on the LPR.

Inhibition of the Late Phase Response to Anti‐IgE in Humans by Indomethacin

The hypothesis of cyclooxygenase derivates of arachidonic acid as putative mediators of late phase skin reactions (LPR) was evaluated by studying the effect of indomethacin and naproxen on anti-IgE elicited skin reactions in healthy volunteers. Indomethacin 50 mg t.i.d., 48 h prior to and up to 24 h following challenge with anti-IgE 1/3300 (v/v), produced a slight attenuation of the flare response and a 35% inhibition of the LPR (P less than 0.05) at 1-24 h as compared with placebo (n = 11). Naproxen, 250 mg, b.i.d. showed analogous anti-LPR effect (n = 4, P less than 0.05). Intradermally (i.d.) injected indomethacin, 75 micrograms (7 X 10(-3) mol/l), attenuated the flare and LPR to anti-IgE 1/330 at 1-6 h (n = 12, P less than 0.01). Indomethacin, oral and i.d., enhanced the LPR to various dilutions of anti-IgE in 30% of the individuals. The results suggest that prostaglandins and thromboxanes participate in the development of an LPR in human skin.

The Late Phase Skin Reaction: Evidence for Activation of the Coagulation System in an IgE-Dependent Reaction in Man

Abstract The late phase reaction (LPR), an IgE-dependent sequel to the wheal and flare response (WFR), was studied in ragweed (RW)-sensitive subjects 15 min and 6 to 8 hr after intradermal RW injection. The role of WFR in the genesis of LPR and LPR dependence on RW dose were determined by skin test titration to extinction of LPR. LPR size correlated with WFR size. LPR were noted with WFR as small as 9.5 ± 1.0 mm (S.E.M.) and RW doses as small as 0.01 protein nitrogen unit (PNU). In a group of WFR-positive but LPR-negative subjects, LPR were not induced despite increasing WFR to 18.2 ± 1.3 mm by simultaneous injection of RW + histamine (RW-H). Light microscopy of 1-µm biopsy sections of direct and Prausnitz-Kustner (P-K) LPR revealed a mixed cellular infiltrate qualitatively no different than that seen 6 hr after isolated WFR. Fibrin deposition in the absence of immunoglobulin or complement was seen by fluorescent microscopy in LPR but not in controls. These data suggest that LPR may follow small RW doses. Furthermore, the failure of RW-H injection to induce LPR argues against a gatekeeper role for WFR in the genesis of LPR. The significance of the cellular infiltrate is not clear although fibrin deposition explains the clinical induration of LPR. This fibrin deposition is evidence for activation of the coagulation system in these IgE-dependent “delayed in time” reactions.