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P W Ewan

Publications and source records attributed to P W Ewan.

At least 19 recordsLinked to original sources
PubMed1999

Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone.

Both thalidomide and dexamethasone have been shown to inhibit the production of tumour necrosis factor alpha (TNF-alpha), but little is known of their cellular selectivity. Inhibition of monocyte TNF-alpha expression has been implicated in the clinical efficacy of thalidomide, and it has been suggested that the drug modulates only monocyte-derived cytokines. Given the importance of T lymphocyte responses in immunological disorders in which treatment with thalidomide has been successful, it is pertinent to study the effects of this drug on T cell-derived TNF-alpha. In the present investigations we have examined the influence of both thalidomide and dexamethasone on mitogen-induced elaboration of TNF-alpha by CD3+ peripheral blood mononuclear cells (PBMC) and the T cell line MOLT-4. PBMC from healthy human volunteers were stimulated optimally with phytohaemagglutinin (PHA) in the presence of varying concentrations of thalidomide or dexamethasone, and supernatants assayed for TNF-alpha and interleukin 2 (IL-2). Concurrently, PHA-stimulated PBMC were treated with 1 x 10(-1) mM thalidomide or dexamethasone and the cells fixed, permeabilised, stained with anti-CD3 and anti-TNF-alpha fluorescently labelled antibodies and analysed by flow cytometry. MOLT-4 cells were cultured in the presence or absence of the drugs following activation with phorbol myristate acetate (PMA)/ionophore, and supernatants analysed by enzyme-linked immunosorbent assay (ELISA) for cytokine expression. Thalidomide was found to inhibit PBMC-derived TNF-alpha, but not IL-2. In contrast, dexamethasone down-regulated both TNF-alpha and IL-2 in a dose-dependent manner. Thalidomide and dexamethasone both suppressed intracellular levels of TNF-alpha in CD3+ PBMC, reducing percentages of double positive staining cells by 28 and 52%, respectively, compared with controls. In addition, TNF-alpha production by CD3- PBMC was inhibited by 31% by thalidomide and by 47% by dexamethasone. In order to determine whether thalidomide was acting directly on T cells, or indirectly through effects on accessory cells, TNF-alpha production in the T cell line MOLT-4 was investigated. TNF-alpha secretion by PMA/ionophore activated MOLT-4 cells was reduced by 80% following thalidomide treatment and close to background levels following dexamethasone treatment. To verify that thalidomide was acting selectively to down-regulate TNF-alpha, IL-2 production by MOLT-4 cells was also measured and found to be unaffected by the drug. In contrast, dexamethasone reduced MOLT-4-derived IL-2 levels by 20%. These observations suggest that thalidomide, in addition to its known inhibitory effect on monocyte-derived TNF-alpha, is capable also of down-regulating T cell-derived TNF-alpha in a direct and selective manner. In addition, the inhibition of intracellular levels of TNF-alpha strengthens the evidence that the inhibitory effect of thalidomide is at the level of transcription and/or translation and does not reduce cellular TNF-alpha secretion. Such effects could explain the efficacy of thalidomide treatment in various immunological disorders where T cell activation plays an important role in the pathogenesis of the disease.

CD3 Complex↗
PubMed1998

Anaphylaxis.

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Anaphylaxis↗
PubMed1998

Venom allergy.

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Bee Venoms↗
PubMed1998

Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells.

Immunosuppressive drugs are used routinely to reduce the inappropriate production of cytokines in an immune response. Recent attention has focused on drugs that selectively inhibit specific cytokines. Both thalidomide and dexamethasone have been reported to exhibit immunomodulatory effects on cytokines in vitro. We wished to examine the effects of thalidomide and dexamethasone on the production of cytokines by peripheral blood mononuclear cells (PBMC), following mitogenic stimulation, at the level of both secreted product and mRNA production. PBMC from healthy human volunteers were stimulated optimally with phytohaemagglutinin (PHA) in the presence of varying concentrations of thalidomide and dexamethasone using dimethyl sulphoxide (DMSO) as the solvent. Analysis of supernatants by enzyme-linked immunosorbent assay (ELISA) showed that thalidomide caused a dose-dependent inhibition of the pro-inflammatory cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), maximally reducing production by 20 (P < 0.05) and 30% (P < 0.01), respectively, compared with controls. However, thalidomide did not affect either proliferation or the production of interleukin 2 (IL-2), interleukin 4 (IL-4) or interleukin 10 (IL-10). A slight bell shaped inhibition of interferon gamma (IFN-gamma) was seen which was statistically significant (P < 0.05). In contrast, dexamethasone inhibited markedly the expression of all cytokines tested (IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF-alpha) in dose-dependent fashion, reducing levels to near to background. Reverse transcription-polymerase chain reaction (RT-PCR) analyses showed that thalidomide inhibited selectively the expression of TNF-alpha and IL-6 mRNA, whereas dexamethasone inhibited mRNA levels of all cytokines examined. The data indicate that dexamethasone is a broad range immunosuppressant inhibiting all cytokines tested in a dose-dependent manner at the level of both secreted product and mRNA. Conversely, thalidomide selectively inhibits the production of IL-6 and TNF-alpha. Due to their markedly different effects on cytokine production, and the fact that both drugs act at the level of transcription, we believe they influence separate pathways involved in cytokine gene regulation.

Anti-Inflammatory Agents↗
PubMed1998

The frequency and clinical significance of specific IgE to both wasp (Vespula) and honey-bee (Apis) venoms in the same patient.

BACKGROUND: Changeover from Phadebas RAST to Pharmacia AutoCAP increased double-positivity to both honey-bee and common wasp (vespula) venom in our patients. OBJECTIVE: We examined the frequency of IgE double-positivity, its clinical relevance and utility in investigating potentially allergic patients. METHODS: One hundred and eighty-two patients with hymenoptera allergy were tested using RAST (n = 51) and AutoCAP (n = 131) assays over 4 years. Patients had a history of reactions to vespulae (22), honey-bee (10) and unidentified hymenoptera (vespinae) (7). RESULTS: After changing from RAST to AutoCAP double-positivity increased from 10 (5/ 51) to 30% (39/131) (P < 0.01). RAST and CAP assays gave similar median class results (vespula = 3, honey-bee = 2). Thirty-six CAP patients had systemic reactions of Mueller grade II and above. In vespula-allergic double-positive subjects, high CAP classes (> or = class 3) to honey-bee were common (30%). In 25% the CAP classes were equal. In honey-bee-allergic subjects, all vespula venom CAP IgE was low titre (class 1 or 2) and 20% were equal for both venoms. In 43% of vespinae-allergic patients the CAP class was equal to both (class 2 and 3). In contrast, intradermal skin test double-positivity was uncommon. Double-negative skin test results were common in the CAP double-positive population (22% of honey-bee-allergic, 13% of vespula-allergic and 43% of vespinae-allergic patients). Vespula allergic patients have higher bee-venom IgE than vice versa. Twenty-seven per cent of CAP double-positive patients (representing 8% of all venom allergic patients tested over this period) had equal class IgE to both venoms which was not helpful in diagnosis. Combination of skin testing and CAP is unhelpful in only 5/37 (14%) of patients with double-positive serology. CONCLUSION: If used in isolation CAP may be misleading, especially if only one venom is tested. Identification of the causative venom must utilize both clinical history and skin testing in these double-positive patients, and challenge testing if indicated.

Adolescent↗
PubMed1998

Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics.

A new immunoassay system utilizing new automatic instrumentation, new software for evaluation of data, and reagents updated for increased speed and accuracy was evaluated. Six clinical studies included 894 consecutive patients. Major symptoms were rhinoconjunctivitis, asthma, atopic dermatitis, and urticaria. The prevalence of inhalant allergy was 54-69%. Phadiatop, detecting atopic sensitization to common inhalant allergens, agreed with clinical diagnosis in 764/836 cases (91.4%). The clinical sensitivity and specificity were 93% and 89%, respectively. The clinical sensitivity and specificity of UniCAP specific IgE derived from 5170 comparisons with clinical diagnosis were 89% and 91%, respectively. Specific IgE measurements in UniCAP and in the Pharmacia CAP System agreed in 266/274 cases (97%). A comparison of the sensitivity and specificity of Pharmacia CAP System RAST in 1987 and with UniCAP specific IgE in 1995 showed equivalent performance without change of efficacy or degradation of IgE antibodies after 8 years. The systems were equivalent also in terms of measured values (r=0.96, slope=1.12), confirming the standardization of allergens and of assay calibration. UniCAP is an efficient laboratory system for routine diagnostic testing of allergy and a valuable tool for basic studies on allergens and antibodies.

Administration, Inhalation↗
PubMed1997

Management of children with potential anaphylactic reactions in the community: a training package and proposal for good practice.

BACKGROUND: The increase in potentially dangerous food allergic reactions (e.g. to peanuts and nuts) in children had lead to an increase in the prescription of adrenaline, including adrenaline for self- or parent-injection. This raises problems in the management of these children in schools. Our experience in response to this is described. OBJECTIVE: To develop a training package to ensure that each child can continue at school but receive optimum emergency treatment in a safe environment. To provide education, training and support to school staff, and to support parents. METHODS AND RESULTS: This paper describes a model of good practice in the support of children with potentially fatal anaphylactic reactions. The following points are emphasized. Children with a history of anaphylactic reactions should be expertly assessed prior to the prescription of adrenaline injection. A written treatment plan is essential. Parents need expert support in managing the child. Schools need training and support. Children should lead a normal life, and not be stigmatized or labelled by their problem. Close liaison between primary care, acute services, community services and education services are essential for the successful management of this problem. Data from a questionnaire showed the training package was of benefit, with considerable reduction in anxiety in school staff and parents. CONCLUSION: A broad training package is essential: training in administration of adrenaline is only one aspect, and emphasis is placed on education, recognition of allergic reactions and prevention. The presence of children in school needing access to adrenaline is no longer perceived as a problem in our area. We recommend other health authorities provide a similar service.

Anaphylaxis↗
PubMed1996

Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations.

OBJECTIVE: To investigate clinical features of acute allergic reactions to peanuts and other nuts. DESIGN: Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre. SUBJECTS: 62 patients aged 11 months to 53 years seen between October 1993 and September 1994. MAIN OUTCOME MEASURES: Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies. RESULTS: Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods. CONCLUSIONS: Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.

Adolescent↗
PubMed1996

The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department.

We retrospectively studied anaphylaxis in an A&E department from computerized records. In 1993 (Study A), of 55,000 patients seen in casualty, nine had severe anaphylaxis (ANA) with loss of consciousness (LOC) or fainting (about 1: 6000). Fifteen had generalized allergic reactions (GR) without LOC or fainting, but including dyspnoea due to laryngeal oedema or asthma, angioedema and/or urticaria. Thus there were 24 (about 1:2300) generalized reactions involving hypotension and/or respiratory difficulty. A further case diagnosed as hyperventilation syndrome was probably a wasp sting GR. Six cases of urticaria and/or angioedema were also identified. Of the nine with ANA, a possible cause was identified in eight (3 stings; 2 drugs; 3 foods). There was delay in arrival in A&E: hypotension was noted in three and had resolved spontaneously in six. Only 3/9 were related with adrenaline: i.v. hydrocortisone and chlorpheniramine was the mainstay of treatment. No investigation was recommended nor advice given on future management. Four patients were later referred to our allergy clinic by their GPs. In study B (aug-Oct 1994), nine cases of ANA were identified (1:1500), eight due to bee or wasp stings. The increased incidence was probably related to more detailed history-taking. Only three were treated with adrenaline. The use of adrenaline for future anaphylaxis was discussed with six patients, and five were referred to our allergy clinic. A reaction to the same allergen had occurred previously in 24%. Improved awareness of anaphylaxis and its management is necessary.

Adolescent↗
PubMed1995

Twin-to-twin atopy.

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Diseases in Twins↗
PubMed1995

Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy.

BACKGROUND: The mechanism of immunotherapy is unclear. Allergic disease is known to involve enhanced TH-2 cytokine responses to allergen. OBJECTIVE: In order to investigate the mechanisms of immunotherapy, we have examined changes in cytokine secretion before (13 patients) and during (nine patients) both rush and conventional venom immunotherapy (VIT) in bee venom allergic patients. METHODS: Peripheral blood mononuclear cells were stimulated in vitro with bee venom, non-specific antigen or mitogen and secretion of IL-4 (TH-2) and IFN gamma (TH-1) over the culture period measured. RESULTS: Untreated patients had TH-2 responses to venom and TH-1 responses to antigen and strong proliferative responses to venom. Controls showed no response (proliferation or cytokines) to venom and the normal TH-1 response to antigen. VIT resulted in marked changes in cytokine secretion to venom, with reduction of the abnormal TH-2 response and induction of a TH-1 response. The pattern differed in rush and conventional VIT. One day after rush VIT there was a significant fall in IL-4 secretion (P < 0.01), which rose by 3 weeks then declined. In conventional VIT there was a gradual reduction of IL-4 production significant after 2 months and undetectable by 6 months. IFN gamma secretion was induced by VIT. Proliferative responses mirrored the IL-4 changes. One day after rush VIT there was a loss of T cells, monocytes and NK cells from peripheral blood. CONCLUSION: This study shows that immunotherapy shifted cytokine responses to allergen from a TH-2 to a TH-1 dominant pattern, suggesting direct effects on T cells. How these cytokine changes relate to clinical desensitization is not clear. In the longer term they would result in an isotype switch from IgE to IgG. Early changes in cytokine or chemokine production might downregulate mast cell or basophil reactivity and explain the rapid desensitization in rush VIT.

Bee Venoms↗
PubMed1995

The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures.

Thalidomide is an effective immunomodulatory drug in man, but its mechanism of action remains unclear. We hypothesized that, in addition to its reported inhibitory effects on production of monocyte-derived tumour necrosis factor-alpha (TNF-alpha), thalidomide might be effective at the level of Th immunoregulation. In a comparative study with the immunosuppressant cyclosporin A, we have demonstrated a potent and specific effect of thalidomide on cytokine production relating to the distinct Th1 and Th2 subsets. It induced and enhanced the production of IL-4 and IL-5 and, at the same dose (1000 ng/ml), significantly inhibited interferon-gamma (IFN-gamma) production in phytohaemagglutinin (PHA)-stimulated human peripheral blood mononuclear cell (PBMC) cultures. Stimulation of PBMC with recall antigen (streptokinase:streptodornase (SKSD)) at 144 h in the absence of thalidomide resulted in a predominantly Th1 response, with the production of IFN-gamma and IL-2. Thalidomide switched this response from a Th1 to a Th2 type. The effect was most pronounced at 1000 ng/ml thalidomide, where inhibition of IFN-gamma and enhancement of IL-4 production was maximal. In unstimulated cultures thalidomide alone induced IL-4 production. Cyclosporin A, in contrast, inhibited both Th1 and Th2 cytokine production by PHA-stimulated PBMC. Time course data from thalidomide-treated cultures revealed that the augmented IL-4 production diminished as the culture time increased, whereas IFN-gamma production was significantly increased. This response might be due to activation-induced apoptosis of Th2 cells or the induction of Th2 cell anergy, in the continued presence of stimulating agents, with the emergence of IFN-gamma-secreting Th1 cells when Th2 antagonism declines. The effects of thalidomide and related compounds may enhance our understanding of the mechanisms of T helper cell selection, offer the possibility of controlled therapeutic switching between Th1 and Th2 responses, and may lead to a rational approach for the treatment of some T cell-mediated immunological disorders.

Cells, Cultured↗
PubMed1994

The profiles of interleukin (IL)-2, IL-6, and interferon-gamma production by peripheral blood mononuclear cells from house-dust-mite-allergic patients: a role for IL-6 in allergic disease.

We have developed a model to measure cytokine production by peripheral blood mononuclear cells (PBMC) in vitro. In this report, we examine the production of interleukin-2 (IL-2), IL-6, and interferon-gamma (IFN-gamma) by PBMC of house-dust-mite (Dermatophagoides pteronyssinus)-allergic subjects. When stimulated with specific allergen (D. pteronyssinus), PBMC of patients produced significant levels of IL-2 and high levels of IL-6, but little or no IFN-gamma. Nonatopic control PBMC also produced IL-6, although at lower levels, but no IL-2 or IFN-gamma. A ubiquitous antigen, streptokinase/streptodornase (SKSD), induced high levels of IL-2 in patients, but only low levels of IFN-gamma and IL-6. Nonatopic controls produced similar levels of IL-2 and IL-6, but high levels of IFN-gamma to SKSD. IL-2 and IFN-gamma levels induced by the T-cell mitogen phytohaemagglutinin (PHA) were similar in patient and control groups, but IL-6 levels were significantly lower in the patients. IgE synthesis in vitro was shown only in atopic PBMC cultures stimulated with specific allergen. The major points can be summarized as 1) IL-2 production by atopic patients in response to allergen; 2) IL-6 production to allergen by both atopic and nonatopic patients, but significantly increased in atopic patients; and 3) defective IFN-gamma production by atopic patients to both allergen and antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens↗
PubMed1994

A comparative study of IgG subclass antibodies in patients allergic to wasp or bee venom.

IgG1 and IgG4 antivenom antibody responses were compared in groups of patients who had experienced systemic reactions to wasp (Vespula spp.) or bee stings. Pretreatment serum IgG4 antibody levels were low in both groups, but IgG1 antibodies were significantly raised in bee-allergic patients (P < 0.002), probably reflecting their greater exposure to stings than wasp-reactive patients. No direct or indirect relationships were found, in untreated bee or wasp patients, between IgG1, IgG4, or IgE antibody levels and the severity of a patient's last systemic reaction to a sting. After a 12-week course of venom immunotherapy (VIT), IgG1 antibodies increased significantly only in wasp-sensitive patients (P < 0.001), although both groups responded with marked increases in venom-specific IgG4 (P < 0.01). Wasp-allergic subjects who responded to VIT with high production of specific IgG4 showed the greatest increases (pre- to post-VIT) in IgE antibodies (P < 0.05). This group also demonstrated a direct correlation (P < 0.05) between post-VIT levels of IgE and IgG1 antibodies, a finding contrary to an IgE-immunoregulatory role for IgG1. High levels of venom-specific IgG1 alone, or in combination with IgG4, were not protective in three patients who suffered repeated adverse reactions to bee VIT, showing that absolute levels of IgG subclass antivenom antibodies are not reliably indicative of clinical responsiveness in individual patients.

Adult↗
PubMed1994

Humidity regulation in the management of asthma patients sensitized to house dust mites.

Substances in the faeces of house dust mites are well-recognized as common allergens in the pathogenesis of asthma. There have been many trials of interventions aimed at reducing mite populations in the home, but most have been uncontrolled, too small, or too short to determine with confidence any beneficial effects. Of those which succeeded, very few used methods which reduced mite populations on a permanent basis. House dust mites are sensitive to humidity. Their geographical distribution is closely correlated to the availability of moisture. Very little work has been done on the effects of reducing humidity in the home environment in the long term, with a view to controlling dust mite populations. Two different methods which might reduce humidities to levels which could successfully reduce dust mite numbers are dehumidifiers, and mechanical ventilation with heat recovery (MVHR). To date there has been no work assessing the effectiveness of dehumidifiers and very little (although promising) work on MVHR. We discuss the potential of humidity control as an adjunct to the clinical treatment of asthma.

Animals↗
PubMed1993

Acquired angioedema as the presenting feature of lymphoproliferative disorders of mature B-lymphocytes.

BACKGROUND: Acquired complement component 1 (C1) inhibitor deficiency with consequent angioedema is a rare condition that may indicate an underlying neoplasm of B-lymphocytes or plasma cells. METHODS: Three patients with C1 inhibitor deficiency and late-onset angioedema were studied to establish the presence and to characterize the nature of any underlying lymphoproliferative disorder. RESULTS: Each of the patients was found to have a low-grade B-lineage lymphoma. In one patient, the underlying disorder, best characterized as splenic lymphoma with villous lymphocytes, was occult initially. The other two patients had splenic lymphoma with villous lymphocytes and small lymphocytic lymphoma, respectively. Two of the patients had an immunoglobulin M (IgM) serum paraprotein with cold agglutinin activity; the third patient had no paraprotein, but his cells expressed monoclonal membrane IgM. Two of the patients initially did not require specific anti-lymphoma therapy and responded to therapy with an attenuated androgen; in the third patient, splenectomy and cytotoxic chemotherapy led to resolution of the acquired angioedema. In all three patient, there was considerable delay in diagnosis consequent to lack of awareness of this syndrome. CONCLUSIONS: The presence of a neoplasm of B-lymphocytes was established eventually in all three patients, although in one patient it was occult initially. In each case, the lymphocytes were mature B-lymphocytes that either showed cytologic evidence of plasma cell differentiation or secreted a paraprotein. Underlying lymphoma is common in patients who are seen initially with late-onset angioedema. Angioedema is an important, potentially life-threatening complication of lymphoma. Optimal patient management requires that both angioedema and the underlying lymphoma are recognized.

Aged↗