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The Editors’ Choice
The Editors’ Choice
T HE J OURNAL
Allergy Clinical Immunology AND
Donald Y. M. Leung, MD, PhD Harold S. Nelson, MD Stanley J. Szefler, MD
Getting the real “skinny” on antihistamine distribution Tissue concentrations of medications, including those commonly used for the treatment of allergic disorders, are seldom measured or correlated with pharmacologic activity. In a unique prospective, randomized, double-blind, parallelgroup, single-center study, Simons et al (p 526) measured fexofenadine and diphenhydramine concentrations in skin samples obtained by punch biopsy after initial doses of fexofenadine 120 mg or diphenhydramine 50 mg and at steady state after a week of regular daily dosing with the H1-receptor antagonist. They correlated H1-antagonist skin concen-
Pets and asthma Studies of exposure to pets and risk of asthma have yielded conflicting results. Apelberg et al (p 455) present a systematic review of the 32 eligible studies published by the end of 1999. Although parents of children with asthma are more likely to remove pets from the home, the authors considered an appropriate temporal relationship in the assessment of exposure and effect to be the most critical validity issue. The results suggest that exposure to pets slightly increases the risk of asthma and wheeze in
OF
VOLUME 107
NUMBER 3
trations, plasma concentrations, and cutaneous activity shown by suppression of the histamine-induced wheals and flares. Maximum skin/plasma concentration ratios, 41.3 ± 7.8 for fexofenadine and 8.1 ± 4.4 for diphenhydramine, were obtained 24 hours after the first dose. Fexofenadine penetrated the skin to a significantly greater extent than diphenhydramine at 6, 9, and 24 hours after the initial dose and at 168 hours (steady state), and it resulted in significantly greater wheal suppression at 3, 6, and 9 hours and flare suppression at 3, 6, 9, and 168 hours. On the basis of these data, the efficacy of diphenhydramine should be reexamined in disorders such as chronic urticaria where H1receptor antagonist activity is important.
older children, but this effect is not yet present in preschool children. On the contrary, the risk of wheeze was lower in exposed than unexposed young children, which is consistent with a protective effect but could also be explained by avoidance of pets among parents with allergic diseases. As a whole, very few studies exist that take into account the avoidance and other factors influencing asthma and that evaluate exposure to pets before the onset of asthma. The ideal study would consist of a careful follow-up of children from birth with repeated evaluation of disease status and exposure to pets.
Allergic rhinitis: Interaction between upper and lower airways Allergic rhinitis and asthma are 2 manifestations of the atopic syndrome. Allergic rhinitis often coexists with, and may even precede, allergic asthma. Both diseases are characterized by a similar inflammatory process in which eosinophils are important effector cells. The migration of eosinophils from the blood into the tissues is dependent on adhesion molecules. To date, however, interaction between the upper and lower airways’ inflammatory processes has not been demonstrated. In this issue, Braunstahl et al (p 469) present the results of a nasal allergen provocation study in seasonal allergic rhinitis patients without asthma. They demonstrate that tissue eosinophilia and upregulation of endothelial adhesion molecules, including ICAM-1, VCAM-1, and E-selectin, are present in the nasal and bronchial mucosae of allergic rhinitis subjects 24 hours after nasal allergen provocation. Furthermore, eosinophil and IL-5 levels increase in the peripheral blood after allergen challenge. These inflammatory findings are accompanied by an increase in pulmonary symptoms and a reduction in peak
J ALLERGY CLIN IMMUNOL
A
B
Bronchial mucosal sections stained for VCAM-1 before (A) and after (B) nasal provocation.
expiratory flow. This study shows that allergic rhinitis is not a local inflammatory disease but that the entire respiratory tract is involved even in the absence of clinical asthma.
March 2001 Page 417
Intradermal mycobacterial antigen administration ameliorates atopic dermatitis in children A possible reason for the increasing burden of allergic diseases such as atopic dermatitis, asthma, and allergic rhinitis in the Western world is the reduced exposure of these communities to infections, including tuberculosis, which were rampant throughout most of the world until relatively recently (hygiene hypothesis). If this hygiene hypothesis is correct, administration of these microbial antigens to patients with allergic diseases might ameliorate their symptoms. In this issue, Arkwright et al (p 531)
A show that, in a 3-month randomized, double-blind, place-
bo-controlled trial of 41 children with moderately severe atopic dermatitis, administration of a single dose of killed Mycobacterium vaccae (SRL 172) significantly ameliorated their clinical disease. There were no serious adverse effects, and in no case was the child’s dermatitis made worse by M vaccae administration. If further, larger studies confirm the authors’ findings, administration of these microbial antigens may provide a simple and effective method of not only treating, but possibly also preventing, the aberrant hypersensitivity reactions to usually innocuous antigens that become a common health problem in our relatively sterile, Western urban environments.
Epidermal dendritic cells in atopic dermatitis: A target for tacrolimus ointment? Tacrolimus (FK506) ointment is a novel treatment option for atopic dermatitis (AD). This immunomodulatory macrolactam is known to interact with T cells, mast cells, endothelial cells, and keratinocytes by inhibiting the expression of genes controlled by the nuclear factor NFAT. In this issue, Wollenberg et al (p 519) report their ex vivo data from a clinical trial with tacrolimus ointment, indicating that epidermal dendritic cells (DCs) may be cellular targets for this new compound. They prepared cryosections and epidermal cell suspensions from treated and untreated AD Topical tacrolimus affects the phenotype and function of epidermal DCs in AD. lesions and performed immunohistochemistry, epidermal DC phenotyping, and functional analysis. They found that upon treatment, (1) FcεRI is ed antigen presentation by DCs is assumed to play a critidownregulated in both Langerhans’ cells and the so-called cal role in AD, these data provide new insights into the inflammatory dendritic epidermal cells, (2) inflammatory immunobiology of epidermal DCs in the context of AD and dendritic epidermal cells but not Langerhans’ cells were strongly suggest that a part of the therapeutic effect of depleted from the epidermis, and (3) the stimulatory activtacrolimus may be due to its activity on these cells. ity of the epidermal DCs was reduced. Because IgE-mediat-
IL-10–/– mice reveal potential danger of cytokine therapy in asthma Animal models of asthma show that both IL-12 and IL10 suppress allergen-induced airway changes including eosinophilia and IgE synthesis. IL-12 promotes the synthesis of IL-10, and therefore IL-12’s antiasthma effects might depend on IL-10. On the basis of experiments in IL-10–/– mice, Tournoy et al (p 483) demonstrate that even in the absence of IL-10, treatment with IL-12 remains effective at suppressing allergen-induced airway changes, as shown by an abrogation of the eosinophilia and IgE synthesis. Remarkably, IL-12 treatment induces a severe TH1-driven pulmonary mononuclear cell inflamma-
tion in IL-10–/– mice. The TH2-driven allergen-induced airway inflammation in patients with allergic asthma is characterized by a low IL-12 and IL-10 profile. Therefore a logical therapeutic approach might be to substitute for IL12. However, on the basis of data obtained in this animal model, the authors suggest that reversing the TH2-driven allergen-induced airway inflammation by means of IL-12 might be harmful for patients with asthma because of a TH1-driven pulmonary inflammatory reaction. The authors suggest that newer therapeutic strategies in allergic asthma should aim at selectively inducing tolerance to the allergen-specific TH2 cell, which orchestrates the allergic airway inflammation, rather than at inducing a counterbalancing TH1 reaction.
1/89/113862 Selected articles are indicated in the Table of Contents by EC Page 418 March 2001
J ALLERGY CLIN IMMUNOL
T HE J OURNAL
Allergy Clinical Immunology AND
Donald Y. M. Leung, MD, PhD Harold S. Nelson, MD Stanley J. Szefler, MD
Getting the real “skinny” on antihistamine distribution Tissue concentrations of medications, including those commonly used for the treatment of allergic disorders, are seldom measured or correlated with pharmacologic activity. In a unique prospective, randomized, double-blind, parallelgroup, single-center study, Simons et al (p 526) measured fexofenadine and diphenhydramine concentrations in skin samples obtained by punch biopsy after initial doses of fexofenadine 120 mg or diphenhydramine 50 mg and at steady state after a week of regular daily dosing with the H1-receptor antagonist. They correlated H1-antagonist skin concen-
Pets and asthma Studies of exposure to pets and risk of asthma have yielded conflicting results. Apelberg et al (p 455) present a systematic review of the 32 eligible studies published by the end of 1999. Although parents of children with asthma are more likely to remove pets from the home, the authors considered an appropriate temporal relationship in the assessment of exposure and effect to be the most critical validity issue. The results suggest that exposure to pets slightly increases the risk of asthma and wheeze in
OF
VOLUME 107
NUMBER 3
trations, plasma concentrations, and cutaneous activity shown by suppression of the histamine-induced wheals and flares. Maximum skin/plasma concentration ratios, 41.3 ± 7.8 for fexofenadine and 8.1 ± 4.4 for diphenhydramine, were obtained 24 hours after the first dose. Fexofenadine penetrated the skin to a significantly greater extent than diphenhydramine at 6, 9, and 24 hours after the initial dose and at 168 hours (steady state), and it resulted in significantly greater wheal suppression at 3, 6, and 9 hours and flare suppression at 3, 6, 9, and 168 hours. On the basis of these data, the efficacy of diphenhydramine should be reexamined in disorders such as chronic urticaria where H1receptor antagonist activity is important.
older children, but this effect is not yet present in preschool children. On the contrary, the risk of wheeze was lower in exposed than unexposed young children, which is consistent with a protective effect but could also be explained by avoidance of pets among parents with allergic diseases. As a whole, very few studies exist that take into account the avoidance and other factors influencing asthma and that evaluate exposure to pets before the onset of asthma. The ideal study would consist of a careful follow-up of children from birth with repeated evaluation of disease status and exposure to pets.
Allergic rhinitis: Interaction between upper and lower airways Allergic rhinitis and asthma are 2 manifestations of the atopic syndrome. Allergic rhinitis often coexists with, and may even precede, allergic asthma. Both diseases are characterized by a similar inflammatory process in which eosinophils are important effector cells. The migration of eosinophils from the blood into the tissues is dependent on adhesion molecules. To date, however, interaction between the upper and lower airways’ inflammatory processes has not been demonstrated. In this issue, Braunstahl et al (p 469) present the results of a nasal allergen provocation study in seasonal allergic rhinitis patients without asthma. They demonstrate that tissue eosinophilia and upregulation of endothelial adhesion molecules, including ICAM-1, VCAM-1, and E-selectin, are present in the nasal and bronchial mucosae of allergic rhinitis subjects 24 hours after nasal allergen provocation. Furthermore, eosinophil and IL-5 levels increase in the peripheral blood after allergen challenge. These inflammatory findings are accompanied by an increase in pulmonary symptoms and a reduction in peak
J ALLERGY CLIN IMMUNOL
A
B
Bronchial mucosal sections stained for VCAM-1 before (A) and after (B) nasal provocation.
expiratory flow. This study shows that allergic rhinitis is not a local inflammatory disease but that the entire respiratory tract is involved even in the absence of clinical asthma.
March 2001 Page 417
Intradermal mycobacterial antigen administration ameliorates atopic dermatitis in children A possible reason for the increasing burden of allergic diseases such as atopic dermatitis, asthma, and allergic rhinitis in the Western world is the reduced exposure of these communities to infections, including tuberculosis, which were rampant throughout most of the world until relatively recently (hygiene hypothesis). If this hygiene hypothesis is correct, administration of these microbial antigens to patients with allergic diseases might ameliorate their symptoms. In this issue, Arkwright et al (p 531)
A show that, in a 3-month randomized, double-blind, place-
bo-controlled trial of 41 children with moderately severe atopic dermatitis, administration of a single dose of killed Mycobacterium vaccae (SRL 172) significantly ameliorated their clinical disease. There were no serious adverse effects, and in no case was the child’s dermatitis made worse by M vaccae administration. If further, larger studies confirm the authors’ findings, administration of these microbial antigens may provide a simple and effective method of not only treating, but possibly also preventing, the aberrant hypersensitivity reactions to usually innocuous antigens that become a common health problem in our relatively sterile, Western urban environments.
Epidermal dendritic cells in atopic dermatitis: A target for tacrolimus ointment? Tacrolimus (FK506) ointment is a novel treatment option for atopic dermatitis (AD). This immunomodulatory macrolactam is known to interact with T cells, mast cells, endothelial cells, and keratinocytes by inhibiting the expression of genes controlled by the nuclear factor NFAT. In this issue, Wollenberg et al (p 519) report their ex vivo data from a clinical trial with tacrolimus ointment, indicating that epidermal dendritic cells (DCs) may be cellular targets for this new compound. They prepared cryosections and epidermal cell suspensions from treated and untreated AD Topical tacrolimus affects the phenotype and function of epidermal DCs in AD. lesions and performed immunohistochemistry, epidermal DC phenotyping, and functional analysis. They found that upon treatment, (1) FcεRI is ed antigen presentation by DCs is assumed to play a critidownregulated in both Langerhans’ cells and the so-called cal role in AD, these data provide new insights into the inflammatory dendritic epidermal cells, (2) inflammatory immunobiology of epidermal DCs in the context of AD and dendritic epidermal cells but not Langerhans’ cells were strongly suggest that a part of the therapeutic effect of depleted from the epidermis, and (3) the stimulatory activtacrolimus may be due to its activity on these cells. ity of the epidermal DCs was reduced. Because IgE-mediat-
IL-10–/– mice reveal potential danger of cytokine therapy in asthma Animal models of asthma show that both IL-12 and IL10 suppress allergen-induced airway changes including eosinophilia and IgE synthesis. IL-12 promotes the synthesis of IL-10, and therefore IL-12’s antiasthma effects might depend on IL-10. On the basis of experiments in IL-10–/– mice, Tournoy et al (p 483) demonstrate that even in the absence of IL-10, treatment with IL-12 remains effective at suppressing allergen-induced airway changes, as shown by an abrogation of the eosinophilia and IgE synthesis. Remarkably, IL-12 treatment induces a severe TH1-driven pulmonary mononuclear cell inflamma-
tion in IL-10–/– mice. The TH2-driven allergen-induced airway inflammation in patients with allergic asthma is characterized by a low IL-12 and IL-10 profile. Therefore a logical therapeutic approach might be to substitute for IL12. However, on the basis of data obtained in this animal model, the authors suggest that reversing the TH2-driven allergen-induced airway inflammation by means of IL-12 might be harmful for patients with asthma because of a TH1-driven pulmonary inflammatory reaction. The authors suggest that newer therapeutic strategies in allergic asthma should aim at selectively inducing tolerance to the allergen-specific TH2 cell, which orchestrates the allergic airway inflammation, rather than at inducing a counterbalancing TH1 reaction.
1/89/113862 Selected articles are indicated in the Table of Contents by EC Page 418 March 2001
J ALLERGY CLIN IMMUNOL