Late Cutaneous Allergic Responses Research Articles

Suppression of the early and late cutaneous allergic responses using fexofenadine and montelukast

The relative contribution of histamine and the cysteinyl leukotrienes to the early and late cutaneous allergic responses (ECAR and LCAR) can be studied using antagonists of these mediators. To determine the relative suppression of the ECARs and LCARs using standard doses of an H1-receptor antagonist, a cysteinyl leukotriene1-receptor antagonist, and the two antagonists administered concurrently. We carried out a prospective, randomized, double-blind, placebo-controlled, four-way crossover study in 12 highly allergic participants. Intradermal tests with standardized allergen, and with histamine phosphate, LTD4, and saline controls were performed on 5 different test days as follows: pretreatment baseline and at steady state immediately after the seventh and last dose of a 1-week course of treatment with once-daily fexofenadine, 120 mg; montelukast, 10 mg; fexofenadine and montelukast administered concurrently; or placebo. On each test day, the skin test results were read at intervals from 0.25 to 24 hours after the intradermal injections were performed. After allergen injection, compared with baseline, all treatment regimens significantly decreased the ECAR and LCAR. After allergen injection, compared with placebo, fexofenadine significantly decreased the ECAR and the LCAR from 0.25 to 2 hours and at 8 hours. Montelukast did not significantly decrease the ECAR or LCAR. Fexofenadine and montelukast administered concurrently were not more effective than fexofenadine alone at any time. In the control skin tests, compared with placebo, fexofenadine, but not montelukast, significantly decreased the histamine-induced response, and montelukast, but not fexofenadine, significantly decreased the LTD4-induced response. Fexofenadine and montelukast administered concurrently were not significantly more effective than fexofenadine alone in decreasing the ECAR and LCAR. Montelukast does not need to be discontinued before allergen skin testing. Further studies of the effect of concurrent treatment with higher doses of a histamine antagonist and a leukotriene modifier on the allergic response in the skin are needed.

793 Suppression of the early and late cutaneous allergic responses using the H 1-receptor antagonist montelukast

793 Suppression of the early and late cutaneous allergic responses using the H 1-receptor antagonist montelukast

The skin as a model to study the pathogenesis of IgE-mediated acute and late-phase responses

101. Laroche D, Chrysanthou S, Lefran~ois C, et al. Evidence of a progressive degranulation of basophil in subjects operated on without adverse reaction. Agents Actions 1992;36(suppl C):C199-C200. 102. De Paulis A, Valentini G, Spadaro G, Lupoli S, Tirri G, Marone G. Human basophil releasability. VIII. Increased basophil releasability in patients with scleroderma. Arthritis Rheum 1991;34:1289-96. 103. Yunginger JW, Nelson DR, Squillace DL, et al. Laboratory investigation of deaths due to anaphylaxis. J Forensic Sci 1991;36:857-65. 104. Takeishi T, Martin TR, Katona IM, Finkelman FD, Galli SJ. Differences in the expression of the cardiopulmonary alterations associated with anti-immunoglobulin E-induced or active anaphylaxis in mast cell-deficient and normal mice: mast cells are not required for the cardiopulmonary changes associated with certain fatal anaphylactic responses. J Clin Invest 1991;88:598-608. 105. Sampson HA, Mendelson L, Rosen JP. Fatal and nearfatal anaphylactic reactions to food in children and adolescents [Comments]. N Engl J Med 1992;327:380-4. 106. Shalit M, Schwartz LB, yon Allmen C, Atkins PC, Lavker RM, Zweiman B. Release of histamine and tryptase during continuous and interrupted cutaneous challenge with allergen in humans. J ALLERCY CLIN IMVnJNOL 1990; 86:117-25. 107. Lavker RM, Schechter NM, Guzzo C, Lazarus GS. Aggressive topical corticosteroid therapy: a novel approach to mast-cell-dependent cutaneous disorders. Dermatologica 1987;175:213-6. 108. Lavker RM, Schechter NM, Lazarus GS. Effects of topical corticosteroids on human dermis. Br J Dermatol 1986;115:101-7. 109. Jarjour NN, Calhoun WJ, Schwartz LB, Busse WW. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with increased airway obstruction. Am Rev Resp Dis 1991;144:83-7. 110. Broide DH, Gleich GJ, Cuomo AJ, et al. Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway. J A~LEROY CLlr~ IMMUNOL, 1991; 88:637-48. 111. Liu MC, Bleecker ER, Lichtenstein LM, et al. Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Respir Dis 1990; 142:126-32. 112. Sedgwick JB, Calhoun WJ, Gleich GJ, et al. Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge: characterization of eosinophil and mast cell mediators. Am Rev Respir Dis 1991; 144:1274-81. 113. Liu MC, Hubbard WC, Proud D, et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics: cellular, mediator, and permeability changes. Am Rev Respir Dis 1991;144:51-8. 114. Koshino T, Teshima S, Fukushima N, et al. Identification of basophils by immunohistochemistry in the airways of post-mortem cases of fatal asthma. Clin Exp Allergy 1993;23:919-25.

Isolated late cutaneous skin test response to ampicillin: A distinct entity

A case presentation describes a young woman with a history of two reactions to ampicillin therapy and a reproducible skin test reaction of intermediate timing that disappeared within 48 hours. The skin test response was to ampicillin only and not to other penicillin-related skin test reagents. Tests for serum IgE and IgG antibody to ampicillin were negative. The histology was that of a mononuclear and neutrophilic cellular infiltrate with neutrophil margination in the vessels. There was no immunoglobulin, complement, or fibrin deposition. The skin test reaction began and ended earlier than would be expected for a classic delayed hypersensitivity reaction. It is considered to be an isolated late cutaneous response but cannot yet be designated a late cutaneous allergic response. Reactants characteristic of an Arthus reaction were not present, and no alternative immunologic basis was confirmed.

Cellular inflammatory responces in human allergic skin reactions

To define better the role of inflammation in the response to pollen antigens, we have used our skin chamber model to study inflammatory cells recovered from the sites of ongoing allergic reactions. In 15 atopic subjects, paired skin blister sites were simultaneously challenged with ragweed- or grass-pollen antigen or buffer for 5 hours. There were 10 times as many cells recovered at antigen (20.7 × 10 5) than at buffer (20 × 10 5) sites, p < 0.005; > 97% of the cells recovered were neutrophils. The number of cells recovered at the antigen sites correlated with the total amount of histamine released (r = 0.57; p < 0.05) but not with the extinction dilution skin test reactivity nor with the intensity of the late cutaneous allergic response measured 6 hours after the injection of antigen. Phase-contrast microscopic examination of the cells recovered from the antigen sites demonstrated that 82% to 95% were polarized compared to 0% to 1.5% of autologous blood neutrophils obtained simultaneously from the peripheral blood. Antigen site cells were as capable of serum-dependent phagocytosis as peripheral blood neutrophils. There was no significant difference in the migratory response to buffer, the chemoattractant N-formyl-methionyl-leucyl-phenylalanine, or leukotrine B 4, but there was a significantly decreased response to platelet-activating factor when the cells recovered from antigen sites were compared to autologous blood neutrophils. We conclude that during ongoing allergic cutaneous reactions (1) that we can recover a significantly greater number of neutrophils at antigen than at buffer sites, (2) that these cells are capable of chemotaxis and phagocytosis, (3) that these neutrophils appear morphologically different from neutrophils in the peripheral blood, and (4) that the number of neutrophils recovered correlates with the intensity of the ongoing mast cell response as assessed by mediator release.

Correlations of in vivo mediator release with late cutaneous allergic responses in humans: I. Kinetics of histamine release

To evaluate the contribution of mast cell-derived mediators in the late cutaneous allergic response, the duration and quantity of antigen-induced histamine release was compared to the intensity of the antigen-induced skin reactions in atopic volunteers. Chambers containing either pollen extract or buffer were appended to denuded blister bases for 1 hr and were replaced hourly with buffer for 3 additional hr. These were compared to the extinction dilution skin test titer and to the mean diameters of the 20-minute wheal and induration at 6 and 8 hr after intradermal injection of antigen. Chamber-fluid histamine levels were significantly higher at antigen than at buffer sites throughout the 4 hr. The hourly histamine levels correlated with the size of the induration at 6 and 8 hr but not with the wheal size or skin test titer. We conclude that (1) histamine is released for at least 4 hr at skin sites of antigen challenge as a consequence of prolonged release either from individual or sequentially activated mast cells, and (2) the quantity of histamine released correlates with the intensity of the late-phase skin response. We hypothesize that histamine might be a marker for prolonged release from the mast cell of other mediators that are responsible for the late-phase response.

Induction of late cutaneous reaction by kallikrein injection: comparison with allergic-like late response to compound [formula omitted

Although IgE antibody is able to provoke a late cutaneous allergic response (LCAR), the mechanism of its development is not clear. It seems to involve vasoactive and clotting mediators released from mast cells and basophils. Substances biologically similar to plasma kallikrein (KK), a Hageman factor activator, have been shown to be released by basophils in the course of an IgE-dependent reaction. Because compound 48 80 induces LCAR-like responses in the skin, we compared the ability of tissue KK and compound 48 80 to induce late cutaneous reactions (LCRs). All 40 test subjects showed an immediate wheal and flare reaction (WF) after both KK and 48 80 . The WF was followed by an LCR characterized by diffuse edema, pain, and erythema in 36 of 40 subjects with 48 80 and 26 of 40 with KK. The LCRs evoked by the two agents did not differ in their appearance or in their time of development. These reactions increased until the 5 hr mark, began to decrease at the 10 hr mark, and were gone after 24 hr. Histologic study showed edema and a mixed cell infiltration with fibrin deposition. Challenge of the original injection site and a new site after 1 or 2 wk showed a local refractory state lasting 2 wk. Prednisone almost totally suppressed the LCRs induced by both KK and 48 80 .

Diagnostic significance of late cutaneous allergic responses and their correlation with radioallergosorbent test.

In order to study the clinical significance of late cutaneous allergic responses 178 intracutaneous tests were done on the forearm of forty-three allergic patients with perennial allergy and twelve patients with pollen allergy. The allergen concentration was chosen to give a moderate immediate response with a weal diameter of about 15 mm. Late cutaneous allergic responses (LCAR) were elicited in eighty-two intracutaneous tests in thirty-one patients with perennial allergy and in nine intracutaneous tests in eight patients with pollen allergy, with almost all the allergens frequently responsible for allergy in this area. Their occurrence was found to be related to the size of the immediate reaction. Almost all the patients showing LCAR had positive provocation tests and were clinically sensitive to the corresponding allergen.

Relative refractory state for late cutaneous allergic responses

The late cutaneous allergic response (LCAR) is a usual sequel to the wheal-and-flare (early) response in sufficiently intense cutaneous allergic reactions. Allergic reactions with early and late components were produced in the skin of the forearm by the intracutaneous injection of anti-IgE or allergen. One week later, these sites, which were normal in gross appearance, and separate control sites on the opposite forearm, were injected. At the sites of repeat reactions, the wheal diameter of the early response was the same but the LCAR was considerably smaller than at simultaneously injected control sites. This local relative refractory state for LCAR is immunologically nonspecific in the sense that it was manifest even when the antigen injected the second time had no evident immunologic relationship with the antigen injected initially. The refractory state for LCAR was present at 2 wk after the initial reaction, but it was no longer demonstrable after 3 wk. This local relative refractory state for LCAR may represent an inhibitory control mechanism for allergic reactions in man.

Factors which influence late cutaneous allergic responses

Increased doses of ragweed antigen E, grass pollen extract, and the IgG of sheep antiserum to human IgE (anti-IgE) were injected in intracutaneous tests in humans. With increasing doses of reactants, in individual subjects, there were the expected increases in the sizes of early wheal-and-flare responses; moreover, there was an associated increase in the magnitude and the frequency of late cutaneous allergic responses (LCAR). LCAR were shown to be a usual sequel to allergic reactions of sufficient intensity. In persons with allergic bronchopulmonary aspergillosis, cutaneous responses to Aspergillus fumigatus allergen were compared with responses to other allergens and to anti-IgE; in relation to early wheal-and-flare responses, the corresponding LCAR induced by A. fumigatus were approximately the same size as those induced by the other reactants. Skin reactions induced by the prick test method and by intracutaneous injection were compared; for early responses of given sizes, there were apparently equal tendencies to proceed to LCAR in reactions to allergen in the two types of administration. In one subject, anti-IgE-induced responses in the skin of a forearm with sensory denervation were compared with responses in the other normally innervated forearm. At the denervated site was the expected absence of the early flare but no apparent reduction in LCAR. Similarly, local anesthesia immediately prior to anti-IgE eliminated the flare of the early response but did not prevent the occurrence of a LCAR.

Inhibition by prednisone of late cutaneous allergic responses induced by antiserum to human IgE

Dual cutaneous allergic responses can be induced in human subjects by the intracutaneous injection of antiserum to hitman IgE (AHIGE). Adrenocortical steroid fails to inhibit the AHIGE-induced early wheal-and-flare response but does inhibit the late allergic response. This pattern of inhibition by adrenocortical steroid resembles that known to pertain to allergen-induced dual cutaneous allergic responses.

Late cutaneous allergic responses in isolated IgE-dependent reactions

Relationships between IgE-dependent reactions and late cutaneous allergic responses were examined. Heterologous whole antihuman IgE or its pepsin digest F(ab′)2 product injected intracutaneously produced “immediate” wheal and flare responses followed by late responses. Prausnitz-Küstner reactions were similar in appearance. The late responses were studied morphologically by conventional microscopy and by direct immunofluorescent techniques. The results support the thesis that in man, late cutaneous allergic responses can occur in reactions with an isolated involvement of IgE. There is a discussion of the possible relevance of these observations to antigen-induced allergic reactions in skin and in the respiratory tract.

Relationship between late cutaneous allergic responses and IgE-dependent reactions

Relationship between late cutaneous allergic responses and IgE-dependent reactions