In vivo antigen-induced cutaneous mediator release: Simultaneous comparisons of histamine, tryptase, and prostaglandin D2 release and the effect of oral corticosteroid administration†

Atkins, Paul C.; Schwartz, Lawrence B.; Adkinson, N. Franklin; Allmen, Carolyn von; Valenzano, Mary Carmen; Zweiman, Burton

doi:10.1016/s0091-6749(05)80099-5

Cited by 49 publications

(31 citation statements)

References 25 publications

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“…Intradermal PGD 2 injections trigger wheal and flare responses but do not produce immediate itching [35]. We did not alter basophil histamine release mediated through the IgE receptor or spontaneous histamine release, consistent with past studies that showed that PGD 2 enhances antigen-mediated basophil histamine release but not that from polyclonal IgE receptor crosslinking [51]. Therefore, the improvements in CSU subjects’ itch in our AZD1981 trial may be through indirect actions on mast cells and/or basophils.…”

Section: Discussionsupporting

confidence: 88%

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Oliver

Chichester

Devine

et al. 2019

Int Arch Allergy Immunol

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Background: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. Objective: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H₁-antihistamines. Methods: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D₂ (PGD₂)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. Results: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD₂-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. Conclusions: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD₂-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD₂/CRTh2 pathway will be an effective treatment for CSU.

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Section: Discussionsupporting

confidence: 88%

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Oliver

Chichester

Devine

et al. 2019

Int Arch Allergy Immunol

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“…For example, histamine release during late phase reactions in asthma is not accompanied by 44 the release of mast cell-specific mediators such as PGD2 or tryptase [18], suggesting that basophils are the source of the amine. Similar observations have also been made regarding antigen-induced mediator secretion in the skin [19]. Thus, despite their low number in peripheral blood, basophils are not only recruited to sites of allergic inflammation but their mediators appear to be released in sufficient quantities to contribute to allergic symptoms.…”

Section: Detection Of Basophils In Organs Affected By Allergic Reactionssupporting

confidence: 72%

Human basophils as effectors and immunomodulators of allergic inflammation and innate immunity

Gibbs

2005

Clin. Exper.Med.

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Basophils have often stood in the shadow of their tissue-fixed mast cell counterparts which share some, common features, such as high-affinity IgE receptor expression and the ability to release histamine. That rodent mast cells produce a variety of pro-allergic and inflammatory cytokines has further added to the deception that basophils only play a minor role in allergic inflammation. Surprisingly, in humans, basophils, but not mast cells, appear to be the prime early producers of the Th2-type cytokines IL-4 and IL-13, which perform several crucial functions in initiating and maintaining allergic responses. This putative immunomodulatory role of basophils is supported further by their ability to express CD40 ligand, which, together with IL-4 and IL-13, serve as inductors of B-cell proliferation and class switching to IgE and IgG4. Moreover, human basophils are the main cellular source for rapid IL-4 generation, a mandatory requirement for the development of Th2 responses. Recent specific staining techniques have localised basophils in various tissues affected by allergic diseases and it appears likely, but remains to be proven, that the interaction of basophils, T cells and B cells at these sites propagate pro-allergic immune responses. Additionally, basophil activation is not restricted to antigen-specific IgE crosslinking but can be caused in non-sensitised individuals by parasitic antigens, plant lectins and viral superantigens binding to non-specific IgEs. Finally, the presence of novel IgE-independent receptor targets that cause trafficking and Th2 cytokine release from basophils further underlines their potential role in innate as well as adaptive immunity.

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“…In vitro studies have demonstrated that incubation for 24 h with the potent synthetic glucocorticoid dexamethasone does not inhibit mediator release from human mast cells derived from the lung, intestine or skin [26]. Additionally, in vivo administration of glucocorticoids for periods of 48 h or less fails to reduce the magnitude of early-phase allergic responses, indicating that mast cell degranulation is not inhibited [27]. …”

Section: Discussionmentioning

confidence: 99%

Tryptase as Severity Marker in Drug Provocation Tests

Komericki¹,

Arbab²,

Grims³

et al. 2006

Int Arch Allergy Immunol

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Background: In the absence of objective symptoms, it is difficult to assess an adverse reaction during drug provocation testing. We evaluated the value of serum tryptase levels to distinguish between positive, negative and, even more important, so-called ‘hysterical’ reactions (conversion symptoms). The latter are occasionally observed in drug provocation tests when the patient experiences ambiguous subjective symptoms. Methods: In a prospective single-center study, 303 patients underwent 785 drug provocation tests. Blood was taken for tryptase measurement on each test day before and after drug challenge, and the changes in serum tryptase levels in patients with no reactions were compared with those who experienced immediate reactions to a drug. Results: Thirty-four of 785 drug provocations were clinically judged as being positive. Despite objective symptoms, median serum tryptase values in the afternoon were even lower than baseline levels. However, this decrease was not statistically significant. In the 751 patients suffering no objective reactions, the median values of posttesting tryptase values were statistically significantly decreased as compared with pretesting values. Conclusions: The measurement of serum tryptase levels does not appear to be helpful to differentiate mild allergic or nonallergic reactions from ‘hysterical’ ones. The milder decrease in the group with objective drug reactions might indicate slight mast cell activation in some patients. More severe clinical drug reactions led to stronger mast cell degranulation. Mild reactions did not increase the tryptase levels consistently.

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In vivo antigen-induced cutaneous mediator release: Simultaneous comparisons of histamine, tryptase, and prostaglandin D2 release and the effect of oral corticosteroid administration†

Cited by 49 publications

References 25 publications

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Human basophils as effectors and immunomodulators of allergic inflammation and innate immunity

Tryptase as Severity Marker in Drug Provocation Tests

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