Cutaneous Late Phase Response Research Articles

Role of mast cells in the onset of IgE-mediated late-phase cutaneous response in mice

Background: In mice that are passively sensitized to IgE, cutaneous antigen challenge produces a biphasic response with peaks at 1 and 24 hours after challenge. Objective: We investigated the role of mast cells in the IgE-mediated late-phase reaction in mice. Methods: We histologically and ultrastructurally investigated the morphologic changes of mast cells during the biphasic responses. Results: Degranulation of mast cells, which was observed between 4 and 24 hours after challenge, reached a peak at 8 hours. Piecemeal degranulation was seen during the immediate phase reaction. The number of IL-6–positive mast cells was increased after 4 hours in both IgE-sensitized and unsensitized mice, but positive cells showed a greater increase in sensitized mice and reached a peak after 8 hours. With in situ hybridization experiments, mast cells were positive for IL-6 messenger RNA at 6 hours after challenge. Conclusion: These findings indicate that anaphylactic degranulation of mast cells and the expression of IL-6 mRNA within 4 hours after antigen challenge are important for the onset of the late-phase allergic cutaneous reaction in mice. (J Allergy Clin Immunol 2000;106:S91-8.)

C-C Chemokines in Allergen-Induced Late-Phase Cutaneous Responses in Atopic Subjects: Association of Eotaxin with Early 6-Hour Eosinophils, and of Eotaxin-2 and Monocyte Chemoattractant Protein-4 with the Later 24-Hour Tissue Eosinophilia, and Relationship to Basophils and Other C-C Chemokines (Monocyte Chemoattractant Protein-3 and RANTES)

The relationship of expression of the C-C chemokines eotaxin, eotaxin 2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4 to the kinetics of infiltrating eosinophils, basophils, and other inflammatory cells was examined in allergen-induced, late-phase allergic reactions in the skin of human atopic subjects. EG2+ eosinophils peaked at 6 h and correlated significantly with eotaxin mRNA and protein, whereas declining eosinophils at 24 h correlated significantly with eotaxin-2 and MCP-4 mRNA. In contrast, no significant correlations were observed between BB1+ basophil infiltrates, which peaked at 24 h, and expression of eotaxin, eotaxin-2, RANTES, MCP-3, and MCP-4 or elastase+ neutrophils (6-h peak), CD3+ and CD4+ T cells (24 h), and CD68+ macrophages (72 h). Furthermore, 83% of eosinophils, 40% of basophils, and 1% of CD3+ cells expressed the eotaxin receptor CCR3, while eotaxin protein was expressed by 43% of macrophages, 81% of endothelial cells, and 6% of T cells (6%). These data suggest that 1) eotaxin has a role in the early 6-h recruitment of eosinophils, while eotaxin-2 and MCP-4 appear to be involved in later 24-h infiltration of these CCR3+ cells; 2) different mechanisms may guide the early vs late eosinophilia; and 3) other chemokines and receptors may be involved in basophil accumulation of allergic tissue reactions in human skin.

IL-5 production by allergen-stimulated T cells following grass pollen immunotherapy for seasonal allergic rhinitis.

Grass pollen immunotherapy for the treatment of seasonal allergic rhinitis ('summer hayfever') results in improvement in symptoms, a reduction in the early and late phase responses to allergen provocation and decreased tissue eosinophilia. Immunotherapy may act by altering the pattern of cytokine production by allergen-specific T cells from a 'Th2-type' (IL-4 and IL-5) profile to a 'Th1-type' (interferon-gamma (IFN-gamma)) profile. We set out to determine whether clinical improvement following specific allergen immunotherapy is accompanied by reduced production of the pro-eosinophilic and archetypal 'Th2-type' cytokine, IL-5. Peripheral blood mononuclear cells (PBMC) were isolated from (i) 13 patients who had received 6 or 7 years' continuous conventional immunotherapy with timothy grass pollen (Phleum pratense); (ii) 14 patients who had received 3 or 4 years of conventional immunotherapy followed by 3 years of placebo treatment; (iii) 12 matched seasonal rhinitic patients who had never received immunotherapy; and (iv) 17 non-atopic normal controls. PBMC were stimulated with 20 microg/ml and 200 microg/ml P. pratense extract, or 10 microg/ml of Mycobacterium tuberculosis purified protein derivative (PPD), at 2 x 10(6) cells/ml and 5 x 10(6) cells/ml. IL-5 concentrations in culture supernatants collected after 6 days' culture were measured by ELISA. IL-5 production in response to stimulation with P. pratense extract was highly reproducible and was elevated in both of the immunotherapy treated groups and the untreated rhinitics relative to non-atopic controls (P<0.005 for each group relative to non-atopic controls, under each of the four conditions tested). However, no significant reduction was observed in IL-5 production when immunotherapy treated patients were compared with untreated rhinitic controls. Moreover, abrogation of the cutaneous late-phase responses to allergen following treatment was not associated with reduced IL-5 production by allergen-stimulated peripheral blood T cells. Reduced IL-5 production by peripheral blood T cells may not be necessary for immunotherapy to be effective. Local immunodulation of T cell responses may play a role in this form of treatment.

The inhibitory effect of anti-adhesion molecule antibodies on eosinophil infiltration in cutaneous late phase response in Balb/c mice sensitized with ovalbumin (OVA).

In this study, we investigated the involvement of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), very late activation antigen-4 (VLA-4), lymphocyte function-associated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) on eosinophil infiltration in the cutaneous late phase response (LPR) in OVA-sensitized Balb/c mice by two approaches, immunostaining and inhibition assays with each monoclonal antibody. The eosinophil infiltration into the skin reached a peak at 12 hr after an intradermal challenge with OVA. Infiltrated eosinophils and mononuclear cells in the skin expressed Mac-1 (eosinophils: 38.9 +/- 1.55%, mononuclear cells: 51.2 +/- 2.15%), LFA-1 (eosinophils: 33.3 +/- 0.95%, mononuclear cells: 23.1 +/- 1.07%) and VLA-4 (eosinophils: 14.3 +/- 1.6%, mononuclear cells: 17.2 +/- 1.38%) at 12 h. Intraperitoneal administration of anti-mouse ICAM-1, VCAM-1, and VLA-4 monoclonal antibodies (mAb) before the challenge decreased the eosinophil infiltration by 66.2%, 61.0%, and 54.0%, respectively. On the other hand, pretreatment with anti-mouse LFA-1 mAb or Mac-1 mAb did not significantly decrease the infiltration. These results suggest that VCAM-1/VLA-4 interaction and ICAM-1 play important roles in eosinophil infiltration in cutaneous LPR.

008 The inhibition of eosinophil infiltration in cutaneous late phase response in BALB/C mice sensitized ovalbumin by anti-adhesion molecule antibodies

008 The inhibition of eosinophil infiltration in cutaneous late phase response in BALB/C mice sensitized ovalbumin by anti-adhesion molecule antibodies

007 The inhibitory effect of IPD-1151T on eosinophil infiltration in cutaneous late phase response in BALB/C mice sensitized with ovalubumin(OVA)

007 The inhibitory effect of IPD-1151T on eosinophil infiltration in cutaneous late phase response in BALB/C mice sensitized with ovalubumin(OVA)

732 Autologous serum skin testing of patients with CIU can produce a cutaneous late phase response

732 Autologous serum skin testing of patients with CIU can produce a cutaneous late phase response

699 Apoptosis of neutrophils (Neu) and eosinophils (Eos) and their ingestion by macrophages is associated with the resolution of allergen-induced cutaneous late phase response (LPR)

699 Apoptosis of neutrophils (Neu) and eosinophils (Eos) and their ingestion by macrophages is associated with the resolution of allergen-induced cutaneous late phase response (LPR)

Preferential recruitment of activated, memory T lymphocytes into skin chamber fluids during human cutaneous late-phase allergic reactions

To determine whether activated memory T lymphocytes (CD3 + CD4 + CD45RO + CD25 + HLA-DR +) preferentially accumulate during the cutaneous IgE-dependent late-phase response, we challenged 10 atopic patients with allergen and monitored the cellular influx for 12 hours with a skin blister chamber model. Four patients with allergy were also challenged with irrelevant allergen in control experiments. Histamine release and the size of the cutaneous late-phase response were measured. Light microscopic analysis and phenotyping of recruited and blood lymphocytes were performed with immunofluorescence and flow cytometry. Antigen challenge induced significant histamine release, a macroscopic late-phase response, and significant cellular influx in the appropriately challenged patients with allergy but not in control subjects. In the control group, only limited phenotypic analyses could be performed, which demonstrated an equivalent percentage of CD3 + CD4 + cells in the chamber fluids compared with blood. In contrast, a higher proportion of CD4 + T lymphocytes and a lower proportion of CD8 + T lymphocytes accumulated in chamber fluids during the late-phase response compared with that present in blood. The vast majority of the recruited T lymphocytes expressed a memory phenotype (CD45RO +) with enhanced percentages of CD25 + and HLA-DR + cells. Also, these cells had increased levels of very late antigen-4 (CD49d/CD29) and reduced levels of L-selectin compared with the same cells in blood. These results demonstrate that allergen challenge of the skin in patients with allergy leads to the preferential accumulation of activated, memory T lymphocytes. The mechanism by which these cells are selectively recruited during cutaneous allergic inflammation remains to be determined. ( J Allergy Clin Immunol 1995;96:57-65.)

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

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Distinguishing features of basophil and neutrophil activation by major basic protein

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INFLUENCE OF GRASS POLLEN IMMUNOTHERAPY ON CELLULAR INFILTRATION AND CYTOKINE EXPRESSION DURING ALLERGEN-INDUCED LATE-PHASE CUTANEOUS RESPONSES

Purpose of the Study. The mechanism by which immunotherapy (IT) provides its beneficial effects are poorly understood. This study examines the effects of grass pollen IT on cellular infiltration and cytokine mRNA expression during allergen induced late phase cutaneous responses. Methods. Forty subjects were enrolled in this double blind, placebo controlled study to receive twice weekly injections of either a standardized grass pollen extract or placebo. Once maintenance was reached, injections were administered monthly for 9 months. Skin biopsies following intradermal infection with Timothy extract were performed prior to and following IT. Monoclonal antibody staining was used to detect surface markers on lymphocytes. In situ hybridization was used to identify cells expressing cytokine mRNA. Findings. Both patient groups were matched for age, disease severity, and duration. Thirty-seven patients (17 placebo, 20 active) completed the study. The treated group had a significant decrease in symptoms, medication use, and size of the immediate and late phase reaction (LPR) after intradermal allergen injection upon completion of the IT. Skin biopsy cell counts from actively treated subjects obtained after subcutaneous allergen challenge showed a significant decrease in T helper and eosinophil cell numbers compared to the placebo group. Increases in the expression of CD25 and HLA-DR (markers of T cell activation) were seen in the treatment group. No differences in amount of HA and IL5 mRNA-expressing cells (TH2) were noted, but there was an increase in IFN-γ and IL2 mRNA expressing cells (ie, TH1) in the actively treated group. A significant correlation was noted between the size of the LPR and the numbers of CD4+ cells in the placebo group.

The effect of immunotherapy on the cutaneous late phase response to antigen

Background: This study used the skin chamber model to evaluate prospectively the effect of immunotherapy (IT) on the cutaneous early and late phase response (LPR) to epicutaneous antigen challenge. Methods: Nine subjects with allergic rhinitis were studied at three time points: before starting IT, after 3 months of IT, and after 6 months of IT. Skin chamber histamine content was measured hourly for 12 hours, and cell counts performed hourly during hours 6 to 12. An intradermal skin test was placed, and the reaction was measured hourly for 12 hours. Skin biopsy specimens were obtained 8 hours after intradermal placement and evaluated for cellular infiltrate and major basic protein deposition. Serum antigen-specific IgG and IgE levels were measured at each time point to confirm physiologic effect of IT. Results: Six months of IT significantly ( p < 0.05) decreased both early and LPR skin test reactivity and skin chamber histamine for hours 1 to 3, 4 to 6, and 9 to 12. Skin chamber LPR cellular influx decreased significantly ( p < 0.05) for neutrophils only. Decrease in LPR histamine after 6 months of IT was significantly correlated with both decrease in mononuclear cells ( R 2 = 0.817, p = 0.002) and decrease in neutrophils ( R 2 = 0.813, p = 0.009). Also significantly correlated were decrease in LPR skin test reactivity, with percent change in skin chamber mononuclear cells ( R 2 = 0.800, p = 0.009) and decrease in early skin test reactivity ( R 2 = 0.675, p = 0.01). Biopsy specimens showed no consistent change in either dermal cellular infiltrate or deposition of major basic protein. Conclusion: IT significantly attenuates cutaneous histamine release and skin test reactivity and is accompanied by a decrease in skin chamber LPR neutrophil influx without significantly altering the dermal infiltrate at 8 hours.

Cutaneous late-phase response in food-allergic children and adolescents with atopic dermatitis.

Food hypersensitivities contribute to disease exacerbation in a sub-group of children with atopic dermatitis (AD). It has been shown that only selected foods are capable of causing clinical reactions when ingested, whereas other foods, to which the patient is equally sensitive by skin-prick testing, may be tolerated. The purpose of this study was to examine the cutaneous late-phase response (LPR) to food antigens in food-allergic patients with AD and to determine if the skin reacted differently to 'relevant foods' (foods eliciting positive skin-prick tests and positive oral challenges) than to 'non-relevant foods' (foods eliciting positive skin tests but negative oral challenges). Using blister chambers adfixed to the skin, six children with AD were challenged epicutaneously with foods to which they had previously been shown to be sensitive. Histamine and PGD2 were measured hourly for 10-12 hr in parallel with quantitation of the cellular traffic. There appeared to be no difference in any of the measured parameters between relevant foods and non-relevant foods, and the patterns of the LPR cells and mediators were similar to those previously described with aero-allergens in patients with respiratory allergy. Histamine rose to 13.0 +/- 24 ng/ml (P < 0.005) during the first hours, declined to < 1 ng/ml by the fifth hour, and then rose a second time to 6.72 +/- 3.4 ng/ml (P < 0.05) during the 12th hour. PGD2 rose to an average of 312 pg/ml (P < 0.05) during the first 3 hr followed by a decline to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-6 is released in the cutaneous response to allergen challenge in atopic individuals

The mechanisms responsible for cutaneous response to antigen are complex. Interleukin-1 (IL-1) and interleukin-6 (IL-6) are proinflammatory cytokines that share many properties. Previous studies with a blister-chamber model have demonstrated IL-1 to be produced in the cutaneous response to antigen. Since IL-2 production by activated T cells and IL-6 production by macrophages are both stimulated by IL-1, we hypothesized that IL-2 and IL-6 may be involved in the cutaneous late-phase response (LPR) to antigen. We examined antigen-challenged sites for IL-2 immunoreactivity (ELISA) but found no difference between antigen- and diluent-challenged skin sites (N = 4). Since IL-2 has been demonstrated to be produced in response to IL-1 and IL-1 activity has been demonstrated to be greatest between hours 10 and 12, we speculated that IL-2 might not be detected until after hour 12. We were unable to demonstrate any increase in IL-2 production, even by extending our studies to 24 hours in two subjects. Antigen-challenged, skin blister-chamber fluids from atopic subjects demonstrated the appearance of IL-6 (ELISA) in pooled samples representing hours 1 1 2 , 3 1 2 , 5 1 2 , and 7, but not at diluent control sites ( p < 0.05; N = 6). IL-6 reached a median peak of 0.66 nglml at 3 1 2 hours. Median levels of IL-6 fell to baseline at 8 hours, followed by a second peak of 0.25 ng/ml at hour 10. Three distinct patterns of IL-6 release were noted: early release of IL-6 followed by a sustained slower rise that peaked at hour 9 before declining to baseline levels at 12 hours, early release of IL-6 followed by a fall to baseline levels at hours 7 to 9 with a second smaller peak at hours 9 to 11, and isolated early release of IL-6. Early IL-6 production correlated with late histamine production (R = 0.801; p = 0.06), and late IL-6 production correlated with eosinophil influx (R = 0.813; p = 0.05). The area of the LPR at skin test sites correlated with early IL-6 peak levels (R = 0.977; p = 0.004) and with total early IL-6 production (R = 0.885; p = 0.05), but not with late IL-6 production. We conclude that IL-6 is released locally in antigen-challenged sites in atopic subjects, that an early monophasic or biphasic release may be observed in individual subjects, and that its degree of early release may play an important role in the pathogenesis of the cutaneous LPR.

Effect of dietary fish oil supplementation on the antigen-induced late-phase response in the skin

We have studied the effect of dietary fish oil supplementation (3.2 gm / day of eicosapentaenoic acid and 2.2 gm/day of docosahexaenoic acid) for 10 weeks on the antigen-induced, cutaneous late-phase response (LPR) in 16 atopic individuals. All subjects developed an LPR to intradermal allergen injection. The mean ± SEM area of induration at 6 hours was 1840 ± 472 mm 2. A biopsy was performed at the LPR site at 6 hours. Subjects were then randomized to receive fish oil or placebo olive oil in a double-blind, parallel fashion, for 10 weeks. After the diet, there were no significant differences between fish oil and placebo treatment in the size of the immediate wheal-and-flare response or the extent of induration at 4 and 6 hours, as compared with prediet values in each group. Histologically, at 6 hours, there was a significant infiltrate into the allergen site compared with that of the control diluent site of total inflammatory cells ( p < 0.002) as well as of eosinophils ( p < 0.001). However, there were no significant differences when pre- and postdiet values were compared. Hence, we conclude that dietary fish oil supplementation does not inhibit the cutaneous LPR clinically or histologically.

Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen.

To better define the effect of systemic glucocorticoids on the cutaneous early and late phase response (LPR), nine atopic subjects were examined in a double-blind cross-over study using skin chambers fixed over denuded skin blisters. A challenge was carried out by placing allergen in the chamber for 60 min in subjects who received either a 3-day pretreatment with 60 mg/day of prednisone or placebo. Skin chamber cell counts and inflammatory mediators (histamine, PGD2, and leukotriene C4 (LTC4)) were measured at hourly intervals for 12 h. Prednisone pretreatment did not alter the immediate skin erythema or release of histamine but ablated the late secondary erythema and rise in histamine. The median histamine values during h 10, 11, and 12 in the placebo and prednisone pretreatment visits were 3.73 and 0.22 ng/ml, respectively (p less than or equal to 0.02). Prednisone did not alter PGD2 production; however, LTC4 production was suppressed during the LPR. The cumulative median LTC4 values during h 7, 8, and 9 were 5.6-fold (p less than or equal to 0.05) more after placebo than after prednisone pretreatment. Prednisone altered cellular traffic more dramatically than it did inflammatory mediators. The influx of eosinophils, which peaked during the 9th and 10th h in placebo-treated patients, was completely blocked by prednisone (p less than or equal to 0.02) for every h from 6 through 12. The influx of basophils, which started during the 9th h and peaked during the 12th h in placebo-treated patients, was suppressed at all time points (p less than or equal to 0.02) in prednisone-treated patients. There was no significant alteration in neutrophil transit into the skin chambers induced by prednisone. We suggest that the selective blockade of eosinophil and basophil influx by prednisone and the associated decrease in inflammatory mediators may contribute to the blockade of the clinical expression of the cutaneous LPR.

Cyclosporin A in atopic dermatitis: therapeutic resonse is disociated form effects on allergic reactons

Fourteen patients with severe chronic atopic dermatitis were treated with cyclosporin A (CyA, Sandimmun; 5 mg/kg/day) for 7-16 weeks. All showed a marked clinical improvement and half could omit topical corticosteroid treatment during therapy. Adverse effects were minor, but two patients relapsed despite continued treatment. In the others, the disease recurred soon after stopping CyA. Serum IgE levels and prick-test responses were unchanged by CyA. Immediate and late-phase cutaneous responses to intradermal house dust mite antigen (HDM) were significantly increased during treatment; but a delayed response, present at 24 and 48 h, was unaffected. Four of six patients challenged with HDM patch tests to tape-stripped skin during treatment showed eczematous reactions at 48 h. Thus, cyclosporin A has a powerful therapeutic effect in atopic dermatitis but does not reduce allergic responses to inhalant antigens.

138 Corticosteroids inhibit the cutaneous late-phase response (LPR) to allergen by blocking the influx of eosinophils and basophils

138 Corticosteroids inhibit the cutaneous late-phase response (LPR) to allergen by blocking the influx of eosinophils and basophils

Cutaneous Late Phase Responses—An Allergic Inflammatory Response

Cutaneous late phase responses have been demonstrated to occur secondary to either immune or nonimmune mast cell activation. In this article I will review studies from our laboratory that support the concept that inflammatory cells, migrating into the allergic reaction secondary to mast cell activation, are themselves activated. These activated cells release mediators that then can induce edematous, indurated cutaneous responses occurring hours after mast cell activation that have been termed "late phase cutaneous responses."