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PubMed1999

Independent replication of pre-clinical research in homeopathy: a systematic review.

OBJECTIVE: To determine whether any pre-clinical research in homoeopathy has been independently replicated. SEARCH STRATEGY: CISCOM was searched using the key words 'homeopathy' and 'basic research'. Further references were obtained from reviews, bibliographies, citation tracking and contact with experts. SELECTION CRITERIA: Studies comparing the effects of one or more homoeopathic medicines to no homoeopathic treatment on any live biological material apart from humans or animals under veterinary care. Research on intoxication and basophil degranulation was excluded. DATA COLLECTION AND ANALYSIS: Publications were grouped in experimental models. Studies were considered to comprise the same model if the outcome variable, biological material and homoeopathic treatment were the same. Publications relating to each experimental model were then arranged in chronological order. A model was considered to have been independently replicated if the first author was different and fewer than half of all authors had previously published research using that model. RESULTS: 120 papers reported 61 different experimental models. Only three models were investigated by different research teams: growth of yeast, growth of wheat coleoptiles and ultra-violet-induced erythema in albino guinea pigs. In the case of yeast, attempts to replicate findings showing increased growth after treatment with Pulsatilla were unsuccessful. For wheat, two experiments by different research teams were conducted, but no single hypothesis was tested in both papers with the same result. Different research teams conducted very similar experiments on erythema treatment by Apis, but the methodological quality of the publications was low. CONCLUSIONS: There is a lack of independent replication of any pre-clinical research in homoeopathy. In the few instances where a research team has set out to replicate the work of another, either the results were negative or the methodology was questionable.

Animals↗

PubMed1999

A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation, survival, and airway eosinophilic inflammation.

Receptor antagonists block all receptor-coupled signaling pathways indiscriminately. We introduce a novel class of peptide inhibitors that is designed to block a specific signal from a receptor while keeping other signals intact. This concept was tested in the model of IL-5 signaling via Lyn kinase. We have previously mapped the Lyn-binding site of the IL-5/GM-CSF receptor common beta (beta c) subunit. In the present study, we designed a peptide inhibitor using the Lyn-binding sequence. The peptide was N-stearated to enable cellular internalization. The stearated peptide blocked the binding of Lyn to the beta c receptor and the activation of Lyn. The lipopeptide did not affect the activation of Janus kinase 2 or its association with beta c. The inhibitor blocked the Lyn-dependent functions of IL-5 in vitro (e.g., eosinophil differentiation from stem cells and eosinophil survival). It did not affect eosinophil degranulation. When applied in vivo, the Lyn-binding peptide significantly inhibited airway eosinophil influx in a mouse model of asthma. The lipopeptide had no effect on basophil histamine release or on the proliferation of B cells and T cells. To our knowledge, this is the first report on an inhibitor of IL-5 that blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. This novel strategy to develop peptide inhibitors can be applied to other receptors.

Amino Acid Sequence↗

PubMed1993

RANTES and related chemokines activate human basophil granulocytes through different G protein-coupled receptors.

Chemotactic cytokines related to interleukin-8 (IL-8; CXC-chemokines) or monocyte chemotactic protein-1 (MCP-1; CC-chemokines) have been shown to stimulate human basophils, and are considered important tissue-derived mediators of inflammation. We have studied the effects of four CC-chemokines and show that MCP-1, RANTES (regulated on activation, normal T expressed and secreted) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are potent basophil agonists inducing a rapid change of cytosolic free calcium ([Ca2+]i), the release of histamine and sulfido-leukotrienes, and chemotaxis. MCP-1 was the most potent stimulus of release, and the only chemokine that induced marked exocytosis in basophils without pretreatment with interleukin-3. RANTES was the strongest stimulus of chemotaxis, but only a moderate stimulus of release. MIP-1 alpha elicited relatively weak chemotaxis and release responses, but was effective at considerably lower concentrations than MCP-1 and RANTES. MIP-1 beta, by contrast, despite its high homology to MIP-1 alpha, was totally inactive. Normodense human eosinophils, tested for comparison, responded in a similar fashion to RANTES and MIP-1 alpha, but were unresponsive to MCP-1 and MIP-1 beta. All CC-chemokines except MIP-1 beta induced a similar rapid and transient rise of [Ca2+]i that was sensitive to pertussis toxin, indicating that they activate basophils via G-protein-coupled receptors. Cross-desensensitization experiments indicate that basophils bear different CC-chemokine receptors. Some interact selectively with MCP-1 or RANTES, while others are shared by RANTES and MIP-1 alpha.

Basophils↗

PubMed1988

A monoclonal antibody that inhibits secretion from rat basophilic leukemia cells and binds to a novel membrane component.

Rat basophilic leukemia (RBL-2H3) cells, like mast cells and basophils, carry monovalent membrane receptors with high affinity for IgE (Fc epsilon R). Cross-linking of these receptors provides the immunologic stimulus which initiates a series of biochemical events, culminating in secretion of inflammatory mediators. In an attempt to identify membrane components involved in the stimulus-secretion coupling of these cells, hybridomas were produced from splenocytes of mice immunized with intact RBL-2H3 cells. Here we report the production of a mAb (designated G63) that inhibits the Fc epsilon R-mediated secretion from RBL cells. At low degrees of Fc epsilon R aggregation, the mAb G63-induced inhibition may be complete, whereas at the maximum of secretion the inhibition is in the range of 30 to 40%. The relative degree of inhibition of secretion is dependent on the dose of mAb G63. Furthermore, inhibition requires the bivalency of G63, as the Fab fragments are inactive. The number of antigenic epitopes recognized by G63 per RBL-2H3 cell is 1.8 x 10(4) epitopes/cell, as determined by direct binding studies of 125I-labeled Fab fragments of G63. This number is 20 to 30 times smaller than that of Fc epsilon R on the same cells. The membrane component to which G63 binds has been identified by immunoprecipitation as a glycoprotein with an apparent Mr of 58 to 70 kDa. All of these results, and the fact that no competition for binding to RBL cells between mAb G63 and IgE can be resolved, indicate that mAb G63 binds to a membrane component which is distinct from the Fc epsilon R. mAb G63 suppresses the Fc epsilon R-mediated rise in cytoplasmic concentration of free Ca2+ ions, known to be one of the biochemical signals involved in the stimulus-secretion coupling in RBL-2H3 cells. G63 does not affect, however, the degranulation induced by the Ca2+ ionophore A23187. Therefore, mAb G63 probably exerts its inhibitory effect on a step preceding the rise in cytoplasmic free Ca2+. Thus, mAb G63 defines a previously unidentified membrane component that is involved in one of the early steps of the RBL-2H3 activation mediated by their Fc epsilon R.

Animals↗

PubMed1993

Skin reactivity in guinea pigs sensitized with 2,4-toluene diisocyanate.

Skin reactivity in guinea pigs sensitized with 2,4-toluene diisocyanate (TDI) has been examined. For sensitization, guinea pigs were treated daily with a 10% TDI solution in ethyl acetate by intranasal application for 5 consecutive days. Local application of TDI onto the flank skin of these TDI-sensitized animals resulted in an immediate development of the flare-and-wheal reaction at the site of application. The extent of the skin response was dependent on the concentration of TDI used for provocation. It was also demonstrated that the skin reactivity was successfully transferred to untreated animals by injecting sera obtained from actively sensitized animals. However, heat treatment of sensitized sera resulted in a slight, but not significant decrease in its ability to sensitize recipient animals. Histological examination revealed degranulation of mast cells and infiltration of basophils and eosinophils in the superficial dermis as the characteristics of the skin reaction in the immediate and late phase, respectively. Pretreatment of TDI-sensitized animals with dexamethasone, a steroidal agent, mepyramine, an antagonist of the histamine H1 receptor, or several antiallergic agents including ketotifen, azelastine and oxatomide resulted in a significant inhibition of the skin reactivity. However, some antiallergic agents such as tranilast, ibuzilast and DSCG were not effective in inhibiting this skin reactivity.

Animals↗

PubMed2002

Proteasome-dependent regulation of Syk tyrosine kinase levels in human basophils.

BACKGROUND: In human basophils, FcepsilonRI signal initiation, leading to histamine release, relies on activation of Syk protein tyrosine kinase. Basophils from approximately 10% of unselected donors do not degranulate in response to FcepsilonRI cross-linking. Their unresponsiveness has been linked to the absence of Syk protein despite apparently normal levels of Syk mRNA. OBJECTIVE: The aim of this study was to explore pathways of Syk protein degradation as a possible posttranslational mechanism for downregulating Syk protein levels in human basophils and other leukocytes. METHODS: Highly purified basophils, lymphocytes, and monocytes were incubated in the presence or absence of a panel of cell-permeable inhibitors of proteolytic degradation pathway(s). Subsequently, the protein level of Syk tyrosine kinase was determined by means of Western blotting. In vitro assays were conducted through use of immunoprecipitated basophil Syk and a rabbit reticulocyte lysate system. RESULTS: Three inhibitors of proteasome-mediated degradation-PSI, lactacystin, and ALLN-substantially increased Syk levels in releaser basophils and restored Syk expression in nonreleaser basophils. Caspase inhibitors were less effective, and inhibitors of calpain-mediated proteolysis had no effect. Among other leukocytes tested, only naive CD4(+) T cells had more Syk after proteasome inhibitor treatment. In vitro ubiquitination assays demonstrated that Syk is readily ubiquitinated in vitro and also that Syk ubiquitination is associated with a substantial decrease in total levels of Syk protein. CONCLUSION: These data provide evidence for a ubiquitin/proteasome-dependent mechanism that contributes to Syk regulation in human basophils and might also be relevant to naive T cells. Understanding this regulatory pathway might lead to strategies for suppressing allergic inflammation while preserving essential Syk-mediated functions in other hematopoietic cells.

Basophils↗

PubMed2004

Echinococcus multilocularis metacestode extract triggers human basophils to release interleukin-4.

Infections with parasitic helminths are associated with a T helper 2 (Th2) immune response and IgE production. The underlying mechanism, however, is only partially understood. Recently we have isolated a protein from extracts of Schistosoma mansoni eggs that triggers human basophils from non-sensitized donors to release interleukin-4 (IL-4), the key cytokine of a Th2 response. We called this protein IPSE (for IL-4-inducing principle from Schistosoma mansoni eggs). Supposing that IPSE-like IL-4-inducing activities might be a general principle shared among different helminth species, we investigated extracts from the cestode E. multilocularis for its effect on human basophils. Our results showed that extracts from metacestodes of E. multilocularis cause basophil degranulation, as well as the secretion of histamine, IL-4 and IL-13, in a dose-dependent manner. IgE stripping and resensitization of basophils indicated that the mechanism of IL-4 induction requires the presence of IgE on the cells. Since analogous properties have been demonstrated earlier for IPSE, we think that S. mansoni and E. multilocularis may induce a Th2 response in their hosts via a related mechanism, namely, by the induction of IL-4 release from basophils.

Animals↗

PubMed2000

Clinical trials results of a unique monoclonal antibody in asthma.

IgE binds to high affinity receptors (Fc epsilon RI) on mast cells, basophils, alveolar macrophages, and antigen-presenting cells. This results in the degranulation of effector cells and the release of mediators, such as histamine, leukotrienes, cytokines, that are causally linked to the pathophysiology of allergic asthma. It made for an attractive target for the development of a unique humanized monoclonal antibody, rhuMAb-E25 (E25). E25 offers a novel strategic approach to allergy treatment, it is expected that using E25 to significantly decrease IgE levels will result in improved control of allergic asthma.

Adult↗

PubMed2004

Non-anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination.

BACKGROUND: Almost 100 million allergic patients are sensitized to the major birch pollen allergen, Bet v 1, a 17 kDa protein containing most of the IgE epitopes present in pollens of trees belonging to the Fagales order and plant-derived food. OBJECTIVE: Our aim was to develop an approach for the rational design of B cell epitope-derived, non-allergenic peptide allergy vaccines. METHODS: According to the three-dimensional (3-D) structure of birch pollen allergen, Bet v 1, six peptides comprising 25-32 preferably solvent-exposed amino acids were synthesized. RESULTS: Because of lack of secondary structure, the peptides showed no allergenic activity in allergic patients. In a mouse model of birch pollen allergy, peptide vaccination induced Bet v 1-specific IgG and prevented IgE-mediated allergic sensitization to Bet v 1. The protective role of peptide-induced blocking antibodies is demonstrated by inhibition of allergic patients IgE binding to the allergen and by blocking of allergen-induced basophil degranulation. CONCLUSION: Our results indicate the mechanistic importance of blocking antibodies for allergy vaccination and present a B cell epitope-based approach for the rational design of safe peptide allergy vaccines whenever the structure of the disease-eliciting allergen is known.

Allergens↗

PubMed1986

Blocking IgG antibodies after rush immunotherapy with mites.

The synthesis of blocking antibodies has been demonstrated in ten patients undergoing rush immunotherapy (R-IT) with mite extracts: basophil degranulation performed on washed cells (Allergolam technique) did not differ significantly before and 10.8 (+/- 6.8) months after R-IT. Preincubation of allergen (100, 25, 10, and 5 micrograms/mL) with individual serum collected before R-IT did not decrease degranulation, but degranulation was significantly decreased when the allergen was incubated 30 minutes at 37 degrees C with individual serum collected after R-IT or with the IgG-fraction of a pool of sera collected in 22 treated patients. A linear correlation between the mean of degranulation and the log allergen concentration was observed in the two latter groups. The antigen neutralizing capacity of the IgG-fraction was studied on basophils of 11 "allergic donors." Antigen neutralizing capacity clearly increased with time of incubation with the allergen (15, 30, and 60 min), but was also significant without preincubation, eg, for 10 and 5 micrograms/mL allergen concentrations. These results indicate that the improvement of asthma usually noticed 2 months after R-IT is probably due, essentially, to blocking antibodies, since the sensitivity of the basophils is not modified significantly.

Adolescent↗

PubMed1986

Effects of ocular inflammation on tear proteins. I. Thiol protease inhibitors.

Concentrations of protease inhibitors found in tears have been observed to vary during ocular inflammation. Possible stimuli for these variations were tested for by studying thiol protease inhibitor concentrations in models of ocular inflammation. Inflammatory responses were elicited either by topical application of arachidonic acid (AA), or compound 48/80. For each model, four rabbits were treated in one eye with the inflammatory stimulant and tear samples were collected before and up to five hours following treatment. Control animals were treated with buffer. When compared to pretreatment values, tears from AA-treated eyes showed decreased inhibitor at one and two hours and an increased inhibitor concentration at three hours. In the 48/80 model, inhibitory activity and protein levels were elevated when compared over time to the control group (p greater than or equal to 0.02, p greater than or equal to 0.0001 respectively). When compared to pretreatment values, inhibitor values were elevated at all times after treatment and protein values were elevated at one and three hours in this model. Serum proteins were also increased in the tears of rabbits treated with 48/80. The results suggest that one or more of the mediators released by basophil or mast cell degranulation stimulate increased tear protease inhibitory activity and tear serum proteins.

Animals↗

PubMed2005

Novel type of Gq/11 protein-coupled neurosteroid receptor sensitive to endocrine disrupting chemicals in mast cell line (RBL-2H3).

1 Agonistic neurosteroids, including pregnenolone, dehydroepiandrosterone and its sulfate (DHEAS), caused rapid degranulation in measurements of beta-hexosaminidase (beta-HEX) release from a mast cell line, RBL-2H3. This degranulation was blocked by BSA-conjugated progesterone (PROG-BSA) or 17beta-estradiol, both of which are antagonistic neurosteroids. 2 DHEAS-induced beta-HEX release was blocked by U-73122 or xestospongin C, but not by PTX or EGTA. DHEAS-induced beta-HEX release was also abolished by G(q/11)-AS, but not by G(q/11)-MS. Pharmacological analyses revealed that the neurosteroids stimulated a putative membrane receptor through activation of the novel G(q/11) and phospholipase C. 3 While representative endocrine-disrupting chemicals (EDCs) did not show any degranulation or nocifensive actions by themselves, they blocked the DHEAS-induced degranulation. 4 The binding of a PROG-BSA-fluorescein isothiocyanate conjugate (PROG-BSA-FITC) to cells was inhibited by neurosteroids and EDCs. 5 In the algogenic-induced biting and licking responses test, DHEAS caused agonistic nocifensive actions in a dose-dependent manner between 1 and 10 fmol (i.pl.). DHEAS-induced nocifensive actions were abolished by PROG-BSA or nonylphenol. 6 Taken together, these results suggest that a G(q/11)-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation and that some EDCs have antagonistic actions for this receptor.

Animals↗

PubMed2003

Negative regulation of Lyn protein-tyrosine kinase by c-Cbl ubiquitin-protein ligase in Fc epsilon RI-mediated mast cell activation.

BACKGROUND: Recent studies have demonstrated that c-Cbl functions as a ubiquitin-protein ligase toward immune receptors and non-receptor protein-tyrosine kinase Syk by facilitating their ubiquitination and subsequent targeting to proteasomes. However, it was not clear whether Src family kinase Lyn is regulated by the Cbl family of ubiquitin-protein ligases. RESULTS: Aggregation of the high affinity IgE receptor (Fc epsilon RI) induces the rapid ubiquitination of Lyn in rat basophilic leukaemia RBL-2H3 cells. Treatment of cells with a proteasome inhibitor enhances the ubiquitination of Lyn. Stimulation of Fc epsilon RI results in the association of Lyn with c-Cbl and Cbl-b, both of which then become tyrosine phosphorylated. Co-transfection study shows that both c-Cbl and Cbl-b could induce the ubiquitination of activated Lyn in COS cells. Furthermore, over-expression of membrane-anchored form of c-Cbl inhibits the Fc epsilon RI-mediated degranulation and cytokine gene production in RBL-2H3 cells by the down-regulation of the kinase activity of Lyn through the enhanced ubiquitination. CONCLUSIONS: These results demonstrate that Lyn is down-regulated by c-Cbl-mediated ubiquitination and subsequent degradation in proteasome after Fc epsilon RI stimulation in mast cells. Targeting of c-Cbl in the lipid raft results in the inhibition of Fc epsilon RI-mediated mast cell activation.

Animals↗

PubMed2002

Classification of anti-FcepsilonRI and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity.

BACKGROUND: Circulating autoantibodies against FcepsilonRI, IgE, or both occur in approximately one third of patients with chronic idiopathic urticaria (CIU), but not all autoantibodies initiate histamine release. OBJECTIVE: We sought to classify patients with CIU into subsets on the basis of serum bioactivity and immunoreactivity and to examine the relationship between newly defined subtype and disease severity. METHODS: Sera from patients with CIU (n = 78), dermog-raphism (n = 15), and cholinergic urticaria (n = 10) and sera from healthy subjects (n = 39) were analyzed by means of Western blot analysis for anti-FcepsilonRI autoantibodies and for histamine release from basophils and dermal mast cells. In vivo reactivity of autologous serum was tested by means of intradermal injection, and CIU severity was determined on the basis of clinical interview. RESULTS: We classified sera from patients with CIU into 5 subsets: immunoreactive histamine-releasing anti-FcepsilonRI autoantibodies (n = 20 [26%]); immunoreactive anti-FcepsilonRI autoantibodies without histamine-releasing activity (n = 12 [15%]); anti-IgE-like autoantibodies (n = 7 [9%]); serum containing a mast cell-specific histamine-releasing factor (n = 7 [9%]); and sera with no identifiable factor (n = 32 [41%]). Patients with serum histamine-releasing activity had more severe urticaria than patients without such activity. Positive skin test responses to autologous sera were associated with histamine-releasing anti-FcepsilonRI autoantibodies but not with non-histamine-releasing anti-FcepsilonRI autoantibodies. Neither healthy subjects nor patients with dermographism or cholinergic urticaria had his-tamine-releasing anti-FcepsilonRI autoantibodies. CONCLUSION: These data support the specificity of functional anti-FcepsilonRI autoantibodies to CIU. The identification of distinctive subsets of patients suggests that other pathogenic mechanisms occur in CIU in addition to direct ligation of FcepsilonRI by autoantibodies causing dermal mast cell degranulation. Elucidating these mechanisms might lead to new treatments for CIU.

Adolescent↗

PubMed1988

Neutrophils and mast cells. Comparison of neutrophil-derived histamine-releasing activity with other histamine-releasing factors.

Human neutrophil-derived histamine-releasing activity (HRA-N) was partially purified and found to contain a heat-stable 1400 to 2300-Da fraction which caused human basophils and rat basophil leukemia cells (RBL) to degranulate. The capacity of HRA-N to activate basophils was not related to the gender or atopic status of the basophil donor, but was related to anti-IgE responsiveness. Several lines of evidence suggest that HRA-N and anti-IgE induce histamine release through distinctly different mechanisms: 1) the time course of HRA-N- and anti-IgE-induced RBL histamine release are different; 2) HRA-N causes histamine release from RBL with and without surface-bound IgE; 3) lactic acid stripping of IgE from human basophils reduces anti-IgE-induced histamine release, but has no consistent effect on HRA-N-induced histamine release; and 4) passive sensitization of lactic acid-stripped basophils with IgE restores anti-IgE-induced histamine release but not HRA-N-induced histamine release. Several histamine-releasing factors (HRF) were compared with HRA-N. Human nasal HRF (HRF-NW, crude and partially purified fractions of 15 to 30, 3.5 to 9, and less than 3.5 kDa), like HRA-N, caused equal histamine release from both native and IgE-sensitized RBL. However, only the 15- to 30-kDa fraction caused histamine release from human basophils in the doses tested. Mononuclear cell HRF (HRF-M, crude and a partially purified 25 kDa Mr fraction) and platelet HRF (HRF-P, crude preparation) failed to cause histamine release from either native or IgE-sensitized RBL but caused 30 +/- 5.5% and 20 +/- 10% net histamine release from human basophils, respectively. HRA-N and HRF-NW were both stable to boiling. These data, taken together, suggest that the capacity of HRA-N to induce RBL and human basophil histamine release and of HRF-NW to stimulate RBL histamine release is independent of IgE. The data further suggest that HRA-N and HRF-NW can be distinguished by size, and that they both differ from mononuclear cell HRF and platelet HRF. Thus, it appears that inflammatory cells generate a family of distinct HRF.

Animals↗

PubMed2002

Dengue virus selectively induces human mast cell chemokine production.

Severe dengue virus infections usually occur in individuals who have preexisting anti-dengue virus antibodies. Mast cells are known to play an important role in host defense against several pathogens, but their role in viral infection has not yet been elucidated. The effects of dengue virus infection on the production of chemokines by human mast cells were examined. Elevated levels of secreted RANTES, MIP-1alpha, and MIP-1beta, but not IL-8 or ENA-78, were observed following infection of KU812 or HMC-1 human mast cell-basophil lines. In some cases a >200-fold increase in RANTES production was observed. Cord blood-derived cultured human mast cells treated with dengue virus in the presence of subneutralizing concentrations of dengue virus-specific antibody also demonstrated significantly (P < 0.05) increased RANTES production, under conditions which did not induce significant degranulation. Chemokine responses were not observed when mast cells were treated with UV-inactivated dengue virus in the presence or absence of human dengue virus-specific antibody. Neither antibody-enhanced dengue virus infection of the highly permissive U937 monocytic cell line nor adenovirus infection of mast cells induced a RANTES, MIP-1alpha, or MIP-1beta response, demonstrating a selective mast cell response to dengue virus. These results suggest a role for mast cells in the initiation of chemokine-dependent host responses to dengue virus infection.

Antibodies, Viral↗

PubMed2005

Antigen-induced reduction in mast cell and basophil functional responses due to reduced Syk protein levels.

BACKGROUND: The high-affinity IgE receptor, FcepsilonRI, is unresponsive on mast cells and basophils from people in several populations through an unknown mechanism. Similarly, FcepsilonRI-positive basophils from 'nonreleasers' are IgE-unresponsive and are deficient in the tyrosine kinase Syk. OBJECTIVE: To test the hypothesis that cross-linking FcepsilonRI on mast cells and basophils leads to FcepsilonRI nonresponsiveness through reduction in Syk protein levels. METHODS: Human mast cells and basophils were used to determine if FcepsilonRI hyporesponsiveness correlated with reduced Syk levels. RESULTS: It is shown that suboptimal antigen challenge, that did not lead to significant mediator release, induced nonresponsiveness and correlated with reduced Syk. Other IgE-associated signaling molecules were unaffected by the same treatment. The ability of IgE-unresponsive mast cells to regain FcepsilonRI responsiveness is paralleled by increased cellular Syk levels in vitro. The reduction of Syk levels with suboptimal antigen concentrations was calcium independent and mediated through a proteasome-dependent mechanism. CONCLUSION: These findings confirm and extend our knowledge about a novel regulatory mechanism for maintaining FcepsilonRI in a quiescent state. This mechanism may also explain why low concentrations of allergen given to patients during allergen immunotherapy induce FcepsilonRI nonresponsiveness and therapeutic benefit without inducing systemic anaphylaxis.

Basophils↗

PubMed1989

Inhibition of the cutaneous response to antigen by a thromboxane-synthetase inhibitor (OKY-046) in allergic dogs.

We studied the effect of a selective thromboxane-synthetase inhibitor, sodium (E)-3-[4-(1-imidazolymethyl)-phenyl]-2-propanoate) (OKY-046) on the late-phase response to antigen in ragweed-sensitized dogs. Skin biopsies were performed before and 1, 6, and 24 hours after ragweed injection. OKY-046 was infused (100 micrograms.kg-1.min) from 1 hour before until 6 hours after intracutaneous ragweed in five dogs. The early clinical response to ragweed (wheal at 20 minutes) was not changed by OKY-046. A late-phase response (induration at 6 hours) was not observed in any of the OKY-046-treated dogs but was present at 6 hours in 4/5 dogs without OKY-046. Typical mast cells responded similarly in both groups with progressive degranulation during 24 hours. Maximal degranulation of atypical mast cells was delayed to 6 hours with OKY-046, whereas these cells responded completely at 1 hour without OKY-046. The inflammatory response to ragweed followed the same pattern in both groups, but the numbers of each cell type were decreased with OKY-046. With OKY-046, the cutaneous response to histamine was not changed significantly from baseline at 6 hours but was increased (p less than 0.05) at 24 hours, whereas without OKY-046, histamine response was significantly increased at 6 hours (p less than 0.001) and 24 hours (p less than 0.01). We conclude that OKY-046 alters the antigen-induced response of atypical mast cells, the subsequent cellular and clinical late-phase response, and prevents the increase in histamine response.

Acrylates↗