Role In Hypersensitivity Reactions Research Articles

In Vivo Cysteinyl Leukotriene Release in Allergic and Nonallergic Immediate Hypersensitivity Reactions during Anesthesia.

Immediate hypersensitivity reactions occurring during anesthesia are classified as allergic when skin tests and mast cell tryptase are positive and as nonallergic when negative results are obtained. Cysteinyl leukotrienes (cysLTs) are potent mediators synthesized by mast cell and eosinophil that induce bronchial constriction. They could play a role in hypersensitivity reactions. cysLT C4, D4, and E4 concentrations were measured by a competition immunoassay in serial plasma samples obtained prospectively from 21 anesthetized controls and retrospectively from 34 patients who reacted at induction of anesthesia (24 with allergic and 10 with nonallergic reactions). In controls, the median (interquartile range) cysLT concentration was 0.83 (0.69 to 1.02) μg/l before anesthesia and was unchanged 30 min, 6 h, and 24 h afterward. In the patients with allergic reactions, the values were highly increased 30 to 60 min after the reaction (17.9 [7.8 to 36.0] μg/l), while the patients with nonallergic reactions had less increased values (7.3 [3.0 to 11.5] μg/l). The difference between the three groups was significant (P < 0.0001). Increased values persisted during the 24 h of observation. Concentrations were significantly higher in patients with bronchospasm (P = 0.016). cysLTs appear to be an important mediator of allergic and nonallergic immediate hypersensitivity reactions. These findings might open a new field for management of patients with hypersensitivity reactions, especially nonallergic ones.

A Role for Mast Cells in Alcohol-Induced Tissue Damage and Remodeling

Introduction: Alcohol continues to be one of the most frequently abused drugs in the world. While low levels of alcohol consumption may have health benefits, chronic abuse of alcohol deleteriously impacts most body systems and contributes to or exacerbates over sixty disease conditions. The mechanisms of organ and tissue damage in response to alcohol abuse include altered metabolic pathways, accumulation of reactive oxygen species and depressed immune function. Mast cells are multi-functional cells that have been classically described for their role in hypersensitivity reactions. More recently, roles for these cells have been elucidated in innate immunity and tissue remodeling. Mast cells perform these functions primarily through the secretion of a plethora of mediators that include histamine, heparin, serine proteases, cytokines and others. The specific factors that are produced and secreted at any time by mast cells depend in part on the tissue microenvironment providing the basis for extensive plasticity of these cells. Recent studies are beginning to define the role of mast cells in mediating the deleterious effects of chronic alcohol abuse. For instance, alcohol-induced damage to the gastrointestinal mucosa is at least in part mediated by activation of mast cells. Pharmacological inhibition of mast cell degranulation attenuates the increased permeability of the gastrointestinal epithelium associated with alcohol abuse. Conclusion: Mast cells and their secretory products have been implicated in promoting a number of disease conditions. Recent studies have suggested an important role for these cells in alcohol-induced tissue remodeling. These cells and their specific secretory mediators may provide novel therapeutic targets in prevention or reversal of alcohol-induced tissue damage.

Measurement of β-tryptase in postmortem serum in cardiac deaths

Mast cells are well known for their role in hypersensitivity reactions. However, there is increasing evidence that they might also participate in both developing and weakening atherosclerotic plaques, potentially causing plaque instability. Some clinical studies have therefore postulated the existence of relationships between blood β-tryptase levels and acute coronary syndromes. In this study, we investigated postmortem serum β-tryptase levels in a series of 90 autopsy cases with various degrees of coronary atherosclerosis that had undergone medico-legal investigations. β-tryptase concentrations in these cases were compared to levels observed in 6 fatal anaphylaxis cases following contrast material administration. Postmortem serum β-tryptase concentrations in the anaphylactic deaths ranged from 146 to 979 ng/ml. In 9 out of 90 cases of cardiac deaths, β-tryptase levels were higher than clinical reference values of 11.4 ng/ml and ranged from 21 to 65 ng/ml. These results indicate that increased postmortem serum β-tryptase levels can be observed, though not systematically, in cardiac deaths with varying degrees of coronary atherosclerosis disease, thereby suggesting that mast cell activation in this disease cannot be ascertained by postmortem serum β-tryptase measurements.

Effect of sugammadex on rocuronium induced changes in pancreatic mast cells

Mast cells play a vital role in hypersensitivity reactions. Rocuronium is known to cause mast cell mobilization, hypersensitivity, and pancreatitis. The aim of this study was to investigate the effects of sugammadex on pancreatic changes due to rocuronium. A total of 42 Sprague-Dawley male rats were divided into six equal groups to receive either rocuronium 1 mg/kg intravenously (i.v., R group), rocuronium 1 mg/kg + sugammadex 16 mg/kg i.v. (RS16 group), rocuronium 1 mg/kg + sugammadex 96 mg/kg i.v. (RS96 group), sugammadex 16 mg/kg (S16), sugammadex 96 mg/kg i.v. (S96 group), or 0.9% sodium chloride (control group). Sugammadex was administered 5s later following rocuronium. In R group, mast count was higher, and the distribution rate of granules and nuclear changes were different compared with other groups. Distribution rate of granules in groups S16 and S96 were similar to the control group and lower compared with other groups. The amount of mast cells and granule density in groups RS16 and RS96 was lower compared with R group. The amount of mast cells in groups RS16 and RS96 was significantly lower compared with other treatment groups. These results suggest that sugammadex may have an inhibitory effect on mobilization and morphological changes in pancreatic mast cells induced by administration of rocuronium and sugammadex in rats.

Granulocytes: New roles for basophils

Expression of high-affinity IgE receptors (FceRI) and histamine-containing granules are hallmarks of basophils, which highlights their similarity to mast cells. Historically, it is this similarity that has focused investigation into the biology of basophils and kept attention on its role in hypersensitivity reactions. Is it possible that there is more to the life of the basophil? Are they more than just terminally differentiated cannon fodder cells rapidly mobilized to repel ecto-parasites using their surface-bound IgE to bind parasite antigens that induce the release of potent mediators? Recent studies of murine basophils by Mack and co-workers published in Nature Immunology1 have begun to suggest that the answer to these questions is yes (Figure 1).

Production and characterisation of monoclonal antibodies to ovine interleukin-5

Monoclonal antibodies (MAbs) were developed against recombinant ovine interleukin-5 (IL-5) produced in the baculovirus expression vector system. One MAb, D11 (isotype IgG1), neutralised the activity of both recombinant and native sources of IL-5 in a biological assay (Baf cell assay) but was only weakly reactive in immunocytochemistry. Conversely, a second MAb, A8 (isotype IgA), successfully detected IL-5 in immunocytochemistry but did not display neutralising activity. The development of these MAbs will enable the assay of ovine IL-5 in vitro and permit studies into the role of hypersensitivity reactions in sheep by neutralisation of IL-5 in vivo.

Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil®): possible role in hypersensitivity reactions

BackgroundPegylated liposomal doxorubicin (Doxil®) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. Patients and methodsPatients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. ResultsModerate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. ConclusionsC activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors.

Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions

We reported earlier that the anticancer drug paclitaxel (Taxol) activated the complement (C) system in human serum in vitro, raising the possibility that C activation might play a role in the ill-understood hypersensitivity reactions (HSRs) to this drug [J. Natl. Cancer Inst. 90 (1998) 300]. In pursuing the mechanism of C activation by Taxol, the present study provided evidence that dilution of the injection concentrate in aqueous solvents led to the formation of micelles and needle-like structures, both of which caused C activation in vitro. Micelles were formed mainly from Cremophor EL (CrEL), the nonionic emulsifier vehicle of paclitaxel, whose level in Taxol infusion exceeded its critical micelle concentration by at least 400-fold. CrEL micelles were shown by quasi-elastic light scattering and cryo-transmission electron microscopy (cryo-TEM) to be spherical with diameters in the 8–22 nm range; however, de novo formation of 50–300 nm microdroplets following incubation with human plasma suggested further fundamental structural transformation in blood. The needle-like structures extended to the multimicron range and were shown by electron diffraction to be crystalline paclitaxel. Taxol-induced C activation was manifested in varying rises of serum C3a-desarg, iC3b and SC5b-9. The causal role of CrEL micelles in C activation was demonstrated by the fact that filtration of aqueous solutions of Taxol or pure CrEL via 30-kDa cutoff filters eliminated, while the filter retentate restored C activation. C activation by Taxol was also inhibited by 10 mg/ml human immunoglobulin (IVIG). If proven clinically, HSRs to Taxol may represent a hitherto vaguely classified adverse drug reaction recently called C activation-related pseudoallergy (CARPA) [Circulation 99 (1999) 2302].

マスト細胞と皮膚腫よう マスト細胞と皮膚腫よう

Mast cells are known as a major normal cellular constituents of dermal connective tissues. They contain an array of biologically active chemical mediators in their granule. Although physiological role of mast cells still remains unclear, they definitely play an important role in hypersensitivity reactions. Apart from typical mast cells in dermal connective tissues (connective tissue mast cells: CTMC), phenotypically distinct mast cell subpopulation, named mucosal mast cells (MMC), has been identified in intestinal and respiratory mucosa. Although phenotypic difference and compartmentalization of CTMC and MMC are clearly seen in mice and rats, our recent observations of Mongolian gerbil mast cells revealed that the phenotypes of mast cell subtypes in this animal was markedly different from those of mice and rats. Similar observation has been reported on human mast cell subsets. Since local mastocytosis or mast cell infiltration is frequently observed in various pathological conditions in the skin, such as ulticaria pigmentosa, neurofibromatosis, keroid, and malignant tumors, cautions should be paled for the characteristics of mast cells involved in the pathophysiology of dermal diseases.

The role of newly formed vessels and cell adhesion molecules in the tissue response to wear products from orthopaedic implants

Neovascularization and activation of endothelial cells play an important role in recruitment of blood leucocytes at sites of inflammation. This study aimed to assess the pattern of vascular growth and the expression of cell adhesion molecules on vascular endothelium and inflammatory macrophages and T cells in the bone-implant interface from patients with aseptically loosened orthopaedic prostheses. ELAM-1, VCAM-1, ICAM-1 and the receptors LFA-1 and CR3 were immunolocalized on cryostat sections of the interface obtained during revision arthroplasty. The results showed that ELAM-1 was restricted to endothelium and was upregulated on different vessels in 21 cases. Its expression correlated strongly with the presence of metal wear debris. VCAM-1 was less frequently expressed (n=6 cases), and was co-expressed with ELAM-1 in three cases with metal debris. ICAM-1 was detected on a large number of vessels on the bone side in 13 cases, but was more strongly expressed on macrophage subsets and foreign body giant cells (FBGCs) on the lining layer at the implant side. This study indicates the contribution of three different pathways in the migration of inflammatory cells to the bone-implant interface in response to phagocytosis of implant degradation products. Upregulated ELAM-1 expression may suggest a role in hypersensitivity reactions. Finally the persistent expression of VCAM-1 and ICAM-1 on macrophages and FBGCs in the lining layer indicates possible cellular interactions with the extracellular matrix proteins.

Histological Study of Mast Cells in the Actively Sensitized Guinea Pig Lung and after Challenge: Effect of a Corticosteroid

Although mast cells are sometimes considered to play a minor role in hypersensitivity reactions, we used a histological method to show the modifications in the guinea pig lung mast cell population in the course of such reactions. We sensitized guinea pigs with ovalbumin and studied the effect of the challenge with and without corticosteroid treatment. We observed that the mast cell count was not modified after sensitization but was decreased after challenge. Twenty-four hours after challenge, the number of mast cells returned to the control value, indicating a renewal of the mast cell pool. A second challenge, 1 week after the first, did not provoke the same mast cell degranulation, suggesting a non-responsiveness to aerosol antigen. Betamethasone dipropionate treatment protected mast cells against challenge: in treated guinea pigs, mast cell degranulation was prevented, and we did not observe any change in mast cell count after challenge. The present study was useful to show an effect of corticosteroids on mast cell degranulation in immediate hypersensitivity reactions in vivo.

Current Perspectives in Allergy

British physicians coined the term hay fever, pioneered the original concepts of allergy, and forged the foundations of treatment. Comparatively recently, their American counterparts rivaled these achievements, especially in the laboratory and field of technology. This book, the collaborative effort of British and American scientists, encompasses the best of both worlds—tradition, theory, and practice—each complementing the other. In clear, explicit, and easily read prose, the authors describe and explain the interactions of the various components of immediate and delayed hypersensitivity responses, the role of hypersensitivity reactions in the pathogenesis of allergic diseases, and the pharmacophysiology of β-adrenergic agents and methylaxanthines. The Americans concentrate on the discovery of IgE, the elucidation of the genetic determinants of IgE immune responses, and the identification of new classes of lipid and peptide mediators of immediate hypersensitivity. The British, who have not labored under Food and Drug Administration constraints, record their experiences and clinical trials

Adjuvancy of Cremophor Elo in rodents.

Cremophor Elo proved as potent as Freund's complete adjuvant for eliciting skin reactivity to bovine serum albumin in guinea pigs. It enhanced delayed hypersensitivity to sheep erythrocytes in mice while hemagglutinin antibody titers were not affected. This adjuvant activity is likely to play a critical role in hypersensitivity reactions to Cremophor-containing drugs, e.g. alphadione.

Eosinophil peroxidase-mediated inactivation of leukotrienes B4, C4, and D4.

The slow-reacting substance (SRS) bioactivity of leukotrienes C4 (LTC4) and D4 (LTD4) was rapidly decreased by incubation with eosinophil peroxidase (EPO), H2O2, and iodide, bromide, or to a lesser degree, chloride, LTB4 chemotactic activity was also decreased by the EPO-H2-H2-halide system, although at a slower rate. Myeloperoxidase could substitute for EPO in these reactions. Leukotriene inactivation was greatly decreased or abolished by deletion of any of the components of the system or by the addition of the hemeprotein inhibitors, azide, cyanide, or aminotriazole, indicating a requirement for peroxidase. The H2O2 concentration employed in the above studies was 10(-4) M. H2O2 at higher concentrations (5 x 10(-4) to 10(-2) M) inactivated LTC4 and LTD4 in the absence of EPO and a halide but had no effect on the chemotactic activity of LTB4. We have previously shown that horse eosinophils stimulated with the calcium ionophore A23187 generate SRS. In the present study, eosinophils stimulated in this way were found to release extracellularly both H2O2 and EPO. Incubation of eosinophils with azide that inhibits EPO, and catalase that degrades H2O2, significantly increased the amount of SRS activity detected in the extracellular medium after A23187 stimulation. These findings suggests eosinophils may play an important modulating role in hypersensitivity reactions both by the production of leukotrienes and by their inactivation through the release of H2O2 and EPO.