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Biomedical subjects

Stephen R Durham

Publications and source records attributed to Stephen R Durham.

At least 37 records · Page 2Linked to original sources
PubMed2004

Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis.

BACKGROUND: Allergic Rhinitis and its Impact on Asthma in collaboration with the World Health Organization initiative reclassified allergic rhinitis, like asthma, by duration and severity. The Xyzal in Persistent Rhinitis Trial is the first large, long-term clinical trial studying patients with persistent rhinitis as defined by Allergic Rhinitis and its Impact on Asthma. OBJECTIVES: Two primary objectives were defined: comparison of the Rhinoconjunctivitis Quality of Life Questionnaire overall score and Total 5 Symptoms Score (rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) over a period of 4 weeks between levocetirizine 5 mg and placebo. Secondary endpoints included similar evaluations at 1 week and 3, 4.5, and 6 months, summary scores for a general health status questionnaire (Medical Outcomes Survey Short Form 36), a pharmacoeconomic assessment, comorbidities, and a safety evaluation. METHODS: The Xyzal in Persistent Rhinitis Trial was a 6-month double-blind, placebo-controlled, multicenter, multinational trial in 551 patients. Adults with persistent rhinitis sensitized to both grass pollen and house dust mite were randomized to receive levocetirizine 5 mg/d or placebo. RESULTS: A total of 421 patients completed the full study. Levocetirizine significantly improved both the Rhinoconjunctivitis Quality of Life Questionnaire overall score and the Total 5 Symptoms Score from week 1 to 6 months (all P values <.001). Medical Outcomes Survey Short Form 36 summary scores were also improved in the levocetirizine group compared with the placebo group. Treatment cessation because of lack of effect, comorbidities, and overall costs of disease, and comorbidities per working patient per month (160.27 vs 108.18) were lower in the levocetirizine group. CONCLUSION: Levocetirizine was shown to improve quality of life and symptoms and to decrease the overall costs of the disease over the 6-month treatment period.

Adolescent↗
PubMed2004

Adjuvants for allergen immunotherapy: experimental results and clinical perspectives.

PURPOSE OF REVIEW: Inclusion of adjuvants in immunotherapy vaccines are important to enhance immune responses to allergens. This article will cover the recent advances in adjuvant formulations described in published articles primarily over the past 2 years. RECENT FINDINGS: Traditionally, allergen immunotherapy preparations utilize aluminium hydroxide as an adjuvant. These have generally proved efficacious and have a good safety profile. However, recent advances in the understanding of immunological mechanisms underlying immunotherapy and in the design of new adjuvants may allow a more rational approach to adjuvant use. One approach is to use adjuvants such as immunostimulatory sequences or monophosphoryl lipid A, which can deviate allergy-associated Th2 immune responses towards a Th1 phenotype. Both of these adjuvants have been used in pilot controlled clinical trials which have demonstrated clinical efficacy and the induction of protective IgG antibodies. Other approaches to improve immunotherapy vaccines include microencapsulation of allergen to allow delivery of the allergen directly to the gut in order to induce immunological tolerance and vaccination with heat-killed mycobacteria. SUMMARY: There is great interest in newly designed adjuvants to improve the efficacy and safety of allergen immunotherapy. A better understanding of immunological mechanisms and further clinical trials utilizing new adjuvants are needed.

Adjuvants, Immunologic↗
PubMed2004

Mechanisms of immunotherapy: IgG revisited.

PURPOSE OF REVIEW: This paper will review historical and recent evidence for the induction of 'blocking' IgG antibodies during successful specific immunotherapy. RECENT FINDINGS: Specific immunotherapy is frequently associated with a rise in allergen-specific IgG4 antibodies and a modest reduction in specific IgE titres, although this does not always correlate with clinical efficacy. There is accumulating evidence that specific immunotherapy also influences the blocking activity on IgE-mediated responses by IgG4, and cellular assays are commonly used to investigate these changes. Recently, a novel assay, which detects allergen-IgE binding using flow cytometry, has been used to detect 'functional' specific immunotherapy-induced changes in IgG antibody activity. Results suggest that successful specific immunotherapy is associated with an increase in IgG blocking activity that is not solely dependent on the quantity of IgG antibodies. SUMMARY: Successful immunotherapy is associated with quantitative and qualitative changes in the allergen-specific IgG antibody response. The induction of IgG antibodies with blocking activity may have a protective role not only through the inhibition of allergen-induced, IgE-mediated release of inflammatory mediators from mast cells and basophils, but also through the inhibition of IgE-facilitated antigen presentation to T cells. Qualitative changes in the allergen-specific IgG antibody response may possibly be an important mechanism underlying the clinical efficacy of specific immunotherapy. Monitoring changes in blocking activity using cellular assays may give an early indication of the potential success of treatment.

Humans↗
PubMed2004

Tregs and allergic disease.

Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4+CD25+ Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high- or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.

Allergens↗
PubMed2004

Mucosal immunity in asthma and chronic obstructive pulmonary disease: a role for immunoglobulin A?

Despite our knowledge on the role of IgA in mucosal homeostasis and host defense and clinical evidence suggesting deficient first-line defense mechanisms in chronic airway disorders, little is known regarding its role in asthma and chronic obstructive pulmonary disease (COPD). Studies suggest that the mucosal IgA response is impaired in COPD, and a deficient transport of IgA across the bronchial epithelium in COPD has been identified, possibly involving neutrophil proteinases, which may degrade the Ig receptor mediating this transepithelial routing. In contrast, the IgA response to allergens in patients with asthma may play a pathogenic role through eosinophil activation. Thus, secretory IgA can induce eosinophil degranulation in vitro, a feature in keeping with the correlations observed in vivo between airway IgA levels and eosinophil cationic protein during late asthmatic responses. Selective IgA deficiency is associated with an increased prevalence of atopy, and a protective role of IgA has been seen in murine models of asthma, delineating the complexity of the IgA system in the airway mucosa. Future studies will hopefully yield better knowledge of IgA biology and lung mucosal immunity and help to use more efficiently the mucosal route for immunotherapy or target specific genes in inflamed airways.

Asthma↗
PubMed2003

Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients.

Immunoglobulin E is produced by nasal B cells in response to allergen. We have analyzed IgE V(H) region sequences expressed in the nasal mucosa of patients suffering from allergic rhinitis. V(H) region sequences were amplified by RT-PCR from IgE(+) B cells from nasal biopsies. In two of six patients, sequence analysis clearly demonstrated the presence of closely related IgE(+) B cell clones: cells displaying identical signature regions across CDR3/FWR4, indicating a common clonal ancestry, but a mixture of shared and diverse somatic mutations across the V(H) region. Furthermore, in one of the two patients exhibiting related IgE(+) B cell clones, five IgA(+) B cell clones, related to the IgE(+) B cell family, were also isolated from the patient's nasal mucosa. This evidence, combined with the local expression of mRNA transcripts encoding activation-induced cytidine deaminase, suggests that local somatic hypermutation, clonal expansion, and class switch recombination occur within the nasal mucosa of allergic rhinitics. The presence of related B cells in the nasal mucosa does not appear to result from the random migration of IgE(+) cells from the systemic pool, as analysis of a nonatopic subject with highly elevated serum IgE did not exhibit any detectable V(H)-Cepsilon transcripts in the nasal mucosa. We have provided evidence that suggests for the first time that the nasal mucosa of allergic rhinitics is an active site for local somatic hypermutation, clonal expansion, and class switch recombination, making it of major significance for the targeting of future therapies.

Adolescent↗
PubMed2003

Activity of human monocytes in IgE antibody-dependent surveillance and killing of ovarian tumor cells.

We have previously shown that a chimeric IgE antibody against the folic acid receptor (MOv18 IgE) inhibits tumor growth in a SCID mouse model of ovarian carcinoma. MOv18 IgE gave greater protection than the corresponding chimeric MOv18 IgG1. We have now confirmed these effects in a nude-mouse model of ovarian carcinoma and have demonstrated for the first time that human monocytes are active in IgE antibody-dependent cell-mediated cytotoxicity. Injection of tumor-bearing mice with PBMC and MOv18 IgE led to infiltration of monocytes into the tumors and prolonged survival of the mice. Incubation of PBMC or purified monocytes and MOv18 IgE with ovarian tumor cells in vitro resulted in tumor cell killing proportional to the expression of unoccupied FcepsilonRI on monocytes.We observed phagocytosis of tumor cells by the monocytes in vitro. Our results suggest that tumor-specific IgE antibodies may be exploited for immunotherapy of cancer.

Animals↗
PubMed2003

The CX3C chemokine fractalkine in allergic asthma and rhinitis.

BACKGROUND: Unlike other chemokines, fractalkine is expressed as a membrane-bound form, mainly on endothelial and epithelial cells, and can be shed as a soluble chemotactic form. Fractalkine can capture leukocytes expressing its receptor (CX(3)CR(1)), including T lymphocytes, rapidly and firmly in an integrin-independent manner. Because of its dual activity, fractalkine plays a major role in the transendothelial and transepithelial migration of leukocytes during inflammation. OBJECTIVE: We sought to study the fractalkine-CX(3)CR(1) axis in patients with allergic airways diseases. METHODS: Plasma fractalkine levels were measured by means of ELISA in 19 control subjects and 55 patients with symptomatic allergic rhinitis, asthma, or both, and CX(3)CR(1) function was studied by using triple-color flow cytometry in circulating T-lymphocyte subpopulations. Segmental allergen challenge was performed in 16 allergic asthmatic patients to analyze fractalkine expression and inflammatory cell recruitment in bronchoalveolar lavage fluid and bronchial biopsy specimens. RESULTS: Compared with control subjects, patients with symptomatic allergic rhinitis and asthmatic patients had increased circulating fractalkine levels, and CX(3)CR(1) function was upregulated in circulating CD4(+) T lymphocytes. Twenty-four hours after segmental allergen challenge, bronchoalveolar lavage fluid soluble fractalkine concentrations increased and correlated with the total number of recruited cells. Bronchial epithelial and endothelial cells expressed high levels of the membrane-bound form of fractalkine before and after challenge. CONCLUSION: Allergic asthma and rhinitis are associated with systemic and bronchial upregulation of the chemotactic axis fractalkine-CX(3)CR(1). This might contribute to the rapid recruitment of circulating CD4(+) T lymphocytes in the airways after allergen stimulation.

Adolescent↗
PubMed2003

Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy.

BACKGROUND: Among atopic individuals, levels of allergen-specific IgG antibodies have been inversely associated with the degree of allergen sensitization. Additionally, allergen-specific IgG antibodies are markedly increased by allergen injection immunotherapy. These observations have led to proposals that allergen-specific IgG antibodies might have protective properties in atopic individuals. OBJECTIVE: We hypothesized that after grass pollen immunotherapy, these antibodies disrupt IgE-dependent allergen processing by antigen-presenting cells. METHODS: We have developed a novel flow cytometric assay based on detection of allergen-IgE binding to the low-affinity IgE receptor on B cells to examine the blocking effects of sera collected from 18 patients who participated in a double-blind, controlled trial of grass pollen immunotherapy for 1 year. RESULTS: In all 10 patients who received active therapy, there was induction of activity that inhibited allergen-IgE binding to B cells (P =.02, vs placebo subjects), as well as subsequent allergen presentation to T cells. This activity copurified with IgG and was allergen specific, because sera taken from patients treated with grass pollen immunotherapy but who were also birch pollen sensitive did not inhibit IgE-birch pollen allergen binding to B cells. CONCLUSION: We conclude that allergen-specific IgG antibodies induced by immunotherapy can disrupt formation of allergen-IgE complexes that bind to antigen-presenting cells and facilitate allergen presentation.

Adult↗
PubMed2003

Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy.

BACKGROUND: Immunotherapy involves the modulation of allergen-specific T-cell responses, either T(H)2-to-T(H)1 immune deviation or, in bee venom-treated patients, induction of IL-10 production by CD4+CD25+ T cells. IL-10-producing CD4+CD25+ regulatory T cells have emerged as potential mediators of immune tolerance in numerous murine models of immunopathology. OBJECTIVE: The aim of this study was to evaluate the role of IL-10 production and CD4+CD25+ T cells in the response to grass pollen immunotherapy. METHODS: PBMCs were isolated from patients after 1 year of grass pollen immunotherapy and from matched untreated atopic and healthy control subjects. After 6 days of in vitro stimulation with Phleum pratense, production of IL-10, IL-5, IL-4, and IFN-gamma and proliferation and numbers of CD4+CD25+ T cells were measured. T cells were then stimulated for a further 5 hours with phorbol 12-myristate 13-acetate and ionomycin and assessed for intracellular IL-10 by means of flow cytometry. RESULTS: Patients undergoing immunotherapy produced significantly more IL-10 than atopic control subjects (patients undergoing immunotherapy, 116 +/- 21 pg/mL [n = 11]; atopic patients, 30 +/- 5 pg/mL [n = 11]; P <.001), and the number of CD4+CD25+ cells identified after allergen stimulation was also greater in the immunotherapy group. The numbers of CD4+CD25+ T cells correlated positively with activation as measured by proliferation in both of the control groups but not in the immunotherapy group. Moreover, only T cells from patients undergoing immunotherapy were positive for intracellular IL-10, and these were almost exclusively CD4+CD25+ cells. CONCLUSION: Grass pollen immunotherapy results in a population of circulating T cells that express the IL-10(+) CD4+CD25+ phenotype in response to allergen restimulation.

Adult↗
PubMed2003

Immunomodulatory treatment strategies for allergic diseases.

Over the last decades the prevalence of allergic disorders, such as hayfever and asthma has increased worldwide, mostly in westernised countries where up to 20 % of the population are affected. The "hygiene hypothesis" suggests that modernised lifestyles such as improved housing conditions, altered dietary habits and smaller family sizes may be responsible for the decrease in infectious and the increase in allergic diseases. Childhood atopic diseases, like eczema, food allergies and recurrent wheezy bronchitis represent a considerable health problem and a major socioeconomic burden due to the chronicity of these disorders. In recent years, a better understanding of the immunopathogenesis of allergic diseases has evolved, which has contributed to the development of novel more targeted forms of therapy. Allergen injection immunotherapy is the only treatment in current use with the potential for modifying the course of allergic disease. In order to better target mucosal allergies, new approaches of administering allergen, via the sublingual or intranasal route, are being developed. The use of modified allergens, allergen peptides, DNA immunization and the use of novel adjuvants represent alternatives to conventional immunotherapy with potential for improved efficacy with less side effects. For atopic asthma, novel treatment strategies aim at locally targeting inflamed airways. Nebulized monoclonal blocking antibodies and soluble interleukin receptors against "Th(2)-type" cytokines have been designed. An alternative approach has been the administration of "Th(1) -type" cytokines. Although, immunomodulatory strategies provide a promising outlook for the treatment of allergic patients, more studies are needed in the future to address issues of efficacy, safety and long-term effects of altered immune responses.

Adjuvants, Immunologic↗
PubMed2002

Increases in allergen-specific IgE in BAL after segmental allergen challenge in atopic asthmatics.

IgE is important in both early and late allergic responses. Increases in the numbers of RNA transcripts coding for IgE have been observed in the bronchial mucosa of asthmatics and in the nasal mucosa of hay fever patients both during natural allergen exposure and after nasal allergen challenge, suggesting that IgE may be synthesized locally in the mucosa. In this study we have examined bronchoalveolar lavage (BAL) taken before and 24 h after bronchoscopic segmental allergen challenge from 18 atopic asthmatic patients, looking for evidence of increases in IgE protein. Allergen-specific IgG and total and allergen-specific IgE were measured in BAL using a fluoroenzyme immunoassay. There was a significant increase in allergen-specific IgE (Ku/L) in the BAL after allergen challenge [before [median (interquartile range)] 0 (0, 0); after 0.35 (0, 1.87): p = 0.009] which was not observed for allergen-specific IgG (p = 1.0) or for IgE specific to an allergen to which the subject was sensitized but was not used for provocation (p = 1.0). Correction for corresponding increases in total IgE, albumin, and urea in BAL did not affect the observed changes in allergen-specific IgE. These data indicate that allergen provocation results in a selective local accumulation of isotype-specific and allergen-specific IgE antibody within the bronchi, independent of alterations in circulating IgE.

Adult↗
PubMed2002

CCR4 in human allergen-induced late responses in the skin and lung.

We studied the regulation of CCR4 expression in peripheral blood and in human models of cutaneous and pulmonary allergen challenge. CCR4 expression was detectable on freshly isolated CD4+ lymphocytes and in CD4+ and CD8+ T cell lines derived from blood of atopic donors. Numbers of CCR4+ cells were up-regulated in T cell lines expanded in the presence of IL-4. CCR4 mRNA was absent at baseline in normal subjects in lung and skin, but present at baseline in the lung of some atopics. Baseline expression of CCR4 mRNA and protein was higher in lung vs. skin, but allergen-induced increases in CCR4 mRNA+ cells were observed in both organs. CCR4 protein+ cells were present at higher levels after allergen challenge in atopics compared to normal subjects. CCR4 may be important in the recruitment of T lymphocytes at sites of allergic inflammation, in a non-organ-specific manner.

Adult↗
PubMed2002

Local IgE synthesis in allergic rhinitis and asthma.

Local IgE production has been a contentious concept for over 40 years. Although a host of clinical observations suggested a local source of IgE, co-localization of IgE to B cells in the nasal mucosa could not be demonstrated. In contrast, igE-producing B cells were observed in local lymphoid tissue. Definitive proof of local IgE synthesis in the nasal mucosa has now become available. Here, we review the recent developments in local IgE research in allergic rhinitis and asthma within their historical context, and speculate on the implications of both local IgE synthesis and ongoing research into local immunoglobulin isotype switching for patient therapy.

Asthma↗
PubMed2002

Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1:Th2 cytokine ratios.

Grass pollen immunotherapy is the only treatment for hayfever that is both effective and confers long-term benefit. Immunotherapy may act by altering the local nasal mucosal T helper type 2 (Th2) to type 1 (Th1) cytokine balance either by down-regulation and/or immune deviation of T-lymphocyte responses. There is controversy as to whether these changes are detectable in peripheral blood. We therefore examined both local nasal and peripheral T-cell responses to allergen exposure in the same subjects before and after immunotherapy. In a double-blind trial of grass pollen immunotherapy, nasal biopsies were obtained at baseline and during the peak pollen season following 2 years of immunotherapy. Placebo-treated patients showed a seasonal increase in CD3(+) T cells (P = 0.02) and in interleukin-5 (IL-5) mRNA(+) cells (P = 0.03) and no change in interferon-gamma (IFN-gamma ) mRNA(+) cells (P = 0.2) in the nasal mucosa. In contrast, in the immunotherapy-treated group, there were no changes in the number of CD3(+) T cells (P = 0.3) and IL-5 mRNA+ cells (P = 0.2) but a significant increase in the number of IFN-gamma mRNA(+) cells (P = 0.03). Furthermore, clinical improvement in the immunotherapy-treated group was accompanied by a seasonal increase in the ratio of IFN-gamma to IL-5 mRNA(+) cells in the nasal mucosa (P = 0.03). In contrast, there were no significant changes in peripheral T-cell proliferative responses or cytokine production for IFN-gamma or IL-5 in response to grass pollen either within or between the two treatment groups. We conclude that successful grass pollen immunotherapy was associated with an increase in the ratio of IFN-gamma to IL-5 mRNA(+) cells in the nasal mucosa, whereas these changes were not reflected by alterations in peripheral blood T-cell proliferative responses or cytokine production before/after treatment.

CD3 Complex↗