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1.
Allergy ; 74(7): 1237-1248, 2019 07.
Article in English | MEDLINE | ID: mdl-30829410

ABSTRACT

Birch and other related trees of the families Betulaceae and Fagaceae (alder, hazel, oak, hornbeam, chestnut, and beech) constitute the birch homologous group. This grouping is primarily based on the extensive IgE cross-reactivity of allergen homologs to the major birch allergen Bet v 1. Birch pollen is the most dominant tree pollen in Northern and Central Europe and is a major cause of allergic rhinitis and, possibly, asthma symptoms. Over the last few decades, levels of birch pollen have risen and the period of exposure has increased due to climate changes. Subsequently, the prevalence of birch pollen sensitization has also increased. The cross-reactivity and sequential pollen seasons within the birch homologous group create a prolonged symptomatic allergy period beyond birch pollen alone. Furthermore, many plant food allergens contain homologs to Bet v 1, meaning that the majority of patients with birch pollen allergy suffer from secondary pollen food syndrome (PFS). As a result, the negative impact on health-related quality of life (HRQoL) in patients allergic to birch pollen is significant. The purpose of this manuscript was to narratively review topics of interest such as taxonomy, cross-reactivity, prevalence, clinical relevance, PFS, and HRQoL with regard to birch pollen allergy from a European perspective.


Subject(s)
Allergens/immunology , Antigens, Plant/immunology , Betula/immunology , Pollen/immunology , Rhinitis, Allergic, Seasonal/epidemiology , Rhinitis, Allergic, Seasonal/immunology , Cross Reactions/immunology , Europe/epidemiology , Humans , Immunization , Immunoglobulin E/immunology , Prevalence , Public Health Surveillance , Rhinitis, Allergic, Seasonal/diagnosis , Seasons , Symptom Assessment
2.
Clin Exp Allergy ; 47(6): 719-739, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28836701

ABSTRACT

Peanut nut and tree nut allergy are characterised by IgE mediated reactions to nut proteins. Nut allergy is a global disease. Limited epidemiological data suggest varying prevalence in different geographical areas. Primary nut allergy affects over 2% of children and 0.5% of adults in the UK. Infants with severe eczema and/or egg allergy have a higher risk of peanut allergy. Primary nut allergy presents most commonly in the first five years of life, often after the first known ingestion with typical rapid onset IgE-mediated symptoms. The clinical diagnosis of primary nut allergy can be made by the combination of a typical clinical presentation and evidence of nut specifc IgE shown by a positive skin prick test (SPT) or specific IgE (sIgE) test. Pollen food syndrome is a distinct disorder, usually mild, with oral/pharyngeal symptoms, in the context of hay fever or pollen sensitisation, which can be triggered by nuts. It can usually be distinguish clinically from primary nut allergy. The magnitude of a SPT or sIgE relates to the probability of clinical allergy, but does not relate to clinical severity. SPT of ≥ 8 mm or sIgE ≥ 15 KU/L to peanut is highly predictive of clinical allergy. Cut off values are not available for tree nuts. Test results must be interpreted in the context of the clinical history. Diagnostic food challenges are usually not necessary but may be used to confirm or refute a conflicting history and test result. As nut allergy is likely to be a long-lived disease, nut avoidance advice is the cornerstone of management. Patients should be provided with a comprehensive management plan including avoidance advice, patient specific emergency medication and an emergency treatment plan and training in administration of emergency medication. Regular re-training is required.


Subject(s)
Arachis/adverse effects , Nut Hypersensitivity/diagnosis , Nut Hypersensitivity/therapy , Nuts/adverse effects , Peanut Hypersensitivity/diagnosis , Peanut Hypersensitivity/therapy , Allergens/immunology , Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/therapeutic use , Antibody Specificity/immunology , Cost of Illness , Diet Therapy/methods , Disease Management , Emergency Medical Services , Humans , Immunoglobulin E/immunology , Immunotherapy/methods , Nut Hypersensitivity/epidemiology , Nut Hypersensitivity/prevention & control , Patient Education as Topic , Peanut Hypersensitivity/epidemiology , Peanut Hypersensitivity/prevention & control , Prevalence , Quality of Life , Risk Factors , Skin Tests/methods , Symptom Assessment
3.
Allergy ; 72(8): 1156-1173, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28152201

ABSTRACT

BACKGROUND: Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. METHOD: The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). RESULTS: All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. CONCLUSIONS: It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.


Subject(s)
Asthma/diagnosis , Asthma/therapy , Conjunctivitis, Allergic/diagnosis , Conjunctivitis, Allergic/therapy , Desensitization, Immunologic , Rhinitis, Allergic/diagnosis , Rhinitis, Allergic/therapy , Allergens/immunology , Asthma/immunology , Basophils/immunology , Basophils/metabolism , Biomarkers , Conjunctivitis, Allergic/immunology , Cytokines/metabolism , Desensitization, Immunologic/methods , Humans , Immunoglobulin E/immunology , Immunoglobulin G/immunology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Prognosis , Rhinitis, Allergic/immunology , Treatment Outcome
4.
Allergy ; 70(8): 933-43, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25903791

ABSTRACT

BACKGROUND: Nonspecific lipid transfer proteins (nsLTPs) represent a major cause of systemic food allergic reactions in the Mediterranean area. This study investigate hierarchical patterns and cluster relationships of IgE sensitization to different nsLTPs, and the relationship to clinical allergy in a large Italian cohort. METHODS: A total of 568 nsLTP-positive subjects after IgE ImmunoCAP-ISAC microarray analysis with Ara h 9, Art v 3, Cor a 8, Jug r 3, Pla a 3, Pru p 3 and Tri a 14 allergens were studied. IgE inhibition experiments were carried out with mugwort and plane tree pollen extracts. RESULTS: Eighty-two per cent of nsLTP-positive participants (94% if <6 years old) were Pru p 3(pos) , and 71% were Jug r 3(pos) . Participants who reacted to >5 nsLTPs reported a higher incidence of food-induced systemic reactions. Only Art v 3 and Pla a 3 (mugwort and plane tree nsLTPs, respectively) were associated with respiratory symptoms, and a correlation was observed between sensitization to pollen and plant food nsLTPs, particularly between Pla a 3 and tree nut/peanut nsLTPs. Co-sensitization to Par j 2 and PR-10 or profilin pan-allergens was associated with a lower prior prevalence of severe food-induced reactions. In inhibition assays, plane and mugwort pollen extracts inhibited 50-100% of IgE binding to food nsLTPs in microarrays. CONCLUSIONS: Testing IgE reactivity to a panel of nsLTP allergens unveils important associations between nsLTP sensitization profiles and clinical presentation and allows the identification of novel cluster patterns indicating likely cross-reactivities and highlighting potential allergens for nsLTP immunotherapy.


Subject(s)
Carrier Proteins/immunology , Food Hypersensitivity/immunology , Food Hypersensitivity/therapy , Immunization/methods , Adolescent , Adult , Aged , Allergens/immunology , Child , Child, Preschool , Cluster Analysis , Cohort Studies , Female , Food Hypersensitivity/physiopathology , Humans , Hypersensitivity/epidemiology , Hypersensitivity/immunology , Hypersensitivity/therapy , Immunoglobulin E/immunology , Italy/epidemiology , Male , Middle Aged , Pollen/immunology , Prevalence , Risk Assessment , Severity of Illness Index , Young Adult
5.
Clin Exp Allergy ; 42(4): 505-12, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22168433

ABSTRACT

Helminth (worm) therapy has already been used in clinical trials associated with allergy. These were generally small scale, safety orientated trials of short duration, justified by epidemiological and experimental data indicating potentially beneficial immune modulation by some parasites. However, parasites by definition are disadvantageous to their hosts, and helminth infection in particular almost invariably induces an allergic phenotype, rendering this somewhat paradoxical therapeutic approach for allergy open to scrutiny. Is parasitic worm therapy for allergy incongruous medicine, or avant-garde medicine? In the present article, we assess the strength of evidence supporting the use of helminth therapy for allergy and critically appraise the trials already completed. Then, should this approach prove successful, we suggest strategies to improve the delivery of helminth therapy, and ways to discover immune response modifiers derived from worms.


Subject(s)
Helminthiasis/immunology , Hypersensitivity/therapy , Therapy with Helminths/methods , Animals , Clinical Trials as Topic , Helminths/immunology , Host-Parasite Interactions/immunology , Humans
6.
Clin Exp Allergy ; 41(9): 1177-200, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21848757

ABSTRACT

Allergic rhinitis (AR) affects more than 20% of the population in the United Kingdom and western Europe and represents a major cause of morbidity that includes interference with usual daily activities and impairment of sleep quality. This guidance prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) is for the management of AR in patients that have failed to achieve adequate relief of symptoms despite treatment with intranasal corticosteroids and/or antihistamines. The guideline is based on evidence and is for use by both adult physicians and paediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are indications and contraindications for immunotherapy, criteria for patient selection, the evidence for short- and long-term efficacy of subcutaneous and sublingual immunotherapy, and discussion on safety and the different modes of immunotherapy including, pre-seasonal and co-seasonal treatments. There are sections on children, allergen standardization, vaccines used in the United Kingdom, oral allergy syndrome, cost effectiveness of immunotherapy and practical considerations of undertaking immunotherapy including recommendations on who should undertake immunotherapy and dosing schedules. Finally, there is discussion on potential biomarkers of response to immunotherapy, the use of component-resolved diagnostics, novel approaches, alternative routes and potential areas for future research.


Subject(s)
Desensitization, Immunologic , Rhinitis, Allergic, Perennial/therapy , Rhinitis, Allergic, Seasonal/therapy , Administration, Cutaneous , Administration, Sublingual , Adult , Allergens/immunology , Child , Contraindications , Cost-Benefit Analysis , Desensitization, Immunologic/adverse effects , Desensitization, Immunologic/economics , Humans , Prognosis , Research , Rhinitis, Allergic, Perennial/diagnosis , Rhinitis, Allergic, Seasonal/diagnosis , Treatment Outcome , United Kingdom
7.
Clin Exp Allergy ; 41(7): 1001-11, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21518043

ABSTRACT

BACKGROUND: Birch pollen-associated oral allergy syndrome, also known as pollen-food syndrome (PFS), is the most common food allergy in adults in the United Kingdom. Because of its characteristic rapid onset of oro-pharyngeal symptoms associated with specific plant foods, it was hypothesized that a history-based questionnaire could accurately diagnose PFS in subjects with rhino-conjunctivitis symptoms in the UK springtime. OBJECTIVE: In this study of diagnostic accuracy, we aimed to validate a simple PFS diagnostic questionnaire and algorithm against a reference diagnostic test method (RTM) comprising diagnosis by expert evaluation of clinical history, skin prick tests and oral food challenge, in subjects reporting allergic rhinitis (AR) in the UK birch pollen season from March to May. METHODS: Participants were UK adults reporting symptoms of spring time-AR (hayfever). They self-completed a diagnostic questionnaire in addition to undergoing an RTM comprising clinical history, skin prick testing to foods and pollens and oral food challenge. Subjects who reported anaphylaxis were excluded on the basis that they required specialist referral. RESULTS: One hundred and twenty three subjects took part in the study. Data from 110 participants were analysed; of the 13 exclusions, four provided insufficient data and nine reported anaphylaxis such that they warranted specialist assessment. Fifty-two participants (47%) were diagnosed with PFS by the RTM in comparison with 51 (46%) by a diagnostic questionnaire and algorithm (P=1.000, McNemar's test). The diagnostic questionnaire and algorithm had a sensitivity of 0.90 (0.78-0.96), a specificity of 0.93 (0.82-0.97), a positive predictive value of 0.92 (0.80-0.97) and a negative predictive value of 0.91 (0.80-0.96) when measured against the RTM. CONCLUSION AND CLINICAL RELEVANCE: The diagnostic questionnaire and algorithm is a practical and robust tool, which enables rapid identification, and therefore management, of individuals with PFS who experience rhino-conjunctivitis symptoms in the UK birch pollen season. Registered with CinicalTrials.Gov. registration number NCT00854958.


Subject(s)
Betula/immunology , Food Hypersensitivity/diagnosis , Malus/immunology , Pollen/immunology , Rhinitis, Allergic, Seasonal/immunology , Surveys and Questionnaires , Adult , Aged , Algorithms , Cross Reactions , Double-Blind Method , Female , Food Hypersensitivity/epidemiology , Food Hypersensitivity/immunology , Humans , Hypersensitivity, Immediate/diagnosis , Hypersensitivity, Immediate/epidemiology , Hypersensitivity, Immediate/immunology , Male , Middle Aged , Rhinitis, Allergic, Seasonal/diagnosis , Rhinitis, Allergic, Seasonal/epidemiology , Sensitivity and Specificity , Skin Tests , Syndrome , United Kingdom , Young Adult
8.
Allergy ; 65(9): 1126-33, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20148806

ABSTRACT

BACKGROUND: CC Chemokine receptor 4 (CCR4) is preferentially expressed on Th2 lymphocytes. CCR4-mediated inflammation may be important in the pathology of allergic rhinitis. Disruption of CCR4 - ligand interaction may abrogate allergen-induced inflammation. METHODS: Sixteen allergic rhinitics and six nonatopic individuals underwent both allergen and control (diluent) nasal challenges. Symptom scores and peak nasal inspiratory flow were recorded. Nasal biopsies were taken at 8 h post challenge. Sections were immunostained and examined by light or dual immunofluorescence microscopy for eosinophils, T-lymphocytes, CCR4(+)CD3(+) and CXCR3(+)CD3(+) cells and examined by in situ hybridization for CCR4, IL-4 and IFN-gamma mRNA(+) cells. Peripheral blood mononuclear cells were obtained from peripheral blood of nine normal donors and the CCR4(+)CD4(+) cells assessed for actin polymerization in response to the CCR4 ligand macrophage-derived chemokine (MDC/CCL22) and the influence of a CCR4 antagonist tested. RESULTS: Allergic rhinitics had increased early and late phase symptoms after allergen challenge compared to diluent; nonatopics did not respond to either challenge. Eosinophils, but not total numbers of CD3(+) T cells, were increased in rhinitics following allergen challenge. In rhinitics, there was an increase in CCR4(+)CD3(+) protein-positive cells relative to CXCR3(+)CD3(+) cells; CCR4 mRNA+ cells were increased and IL-4 increased to a greater extent than IFN-gamma. CCR4(+)CD4(+) T cells responded to MDC in vitro, and this response was inhibited by the selective CCR4 antagonist. CONCLUSION: Lymphocyte CCR4 expression is closely associated with induction of human allergen-induced late nasal responses. Blocking CCR4-ligand interaction may provide a novel therapeutic approach in allergic disease.


Subject(s)
Allergens/immunology , Hypersensitivity, Immediate/immunology , Receptors, CCR4/metabolism , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Seasonal/immunology , Th2 Cells/metabolism , Administration, Intranasal , Adult , Allergens/administration & dosage , Biopsy , Female , Humans , Hypersensitivity, Immediate/physiopathology , Inflammation/immunology , Inflammation/physiopathology , Male , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Receptors, CCR4/genetics , Rhinitis, Allergic, Perennial/physiopathology , Rhinitis, Allergic, Seasonal/physiopathology , Th2 Cells/immunology , Time Factors
9.
Clin Exp Immunol ; 152(3): 440-7, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18422729

ABSTRACT

CCR6 is expressed by multiple leucocyte subsets, including peripheral blood memory T cells, and mouse models implicate a role for this receptor in diverse inflammatory responses that include allergic airway disorders, inflammatory bowel disease and autoimmune encephalitis. In order to study the role of CCR6 in humans, we have investigated the patterns of CCR6 expression and function on T cells from the peripheral blood, skin, nose and lung, in health and in allergic disease. Results show that CCR6 was expressed consistently on a higher proportion of tissue versus peripheral blood-derived CD4+ T cells (P < 0.01). CCR6 was expressed predominantly on CD4+ compared with CD8+ cells in both blood- and tissue-derived T cells (P < 0.001). The number of cells showing CCR6 expression was not proportionally greater in peripheral blood or nasal mucosal T cells of subjects with symptomatic allergic rhinitis. CCR6+ cells demonstrated enhanced functional responses to CCL20 and CCL20 was increased in bronchoalveolar lavage fluid of asthmatics following endobronchial allergen provocation (P < 0.05). Thus, CCR6 may be important in the regulation of T cell recruitment to tissue and up-regulation of CCL20 expression may contribute to the recruitment and/or retention of effector T cells in allergic asthma.


Subject(s)
Asthma/immunology , CD4-Positive T-Lymphocytes/immunology , Chemokine CCL20/metabolism , Receptors, CCR6/metabolism , T-Lymphocyte Subsets/immunology , Adult , Allergens/immunology , Bronchi/immunology , Bronchoalveolar Lavage Fluid/immunology , CD8-Positive T-Lymphocytes/immunology , Cells, Cultured , Chemokine CCL20/immunology , Chemotaxis, Leukocyte , Female , Humans , Male , Nasal Mucosa/immunology , Skin/immunology
10.
Allergy ; 62(1): 59-65, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17156343

ABSTRACT

BACKGROUND: In T cell-associated allergic inflammation, homing of T-helper 2 (Th2) effector cells to mucosal sites may be influenced by chemokine receptor expression. Previous studies have identified CCR3 and CCR4 as putative markers of Th2 cells and CCR5 and CXCR3 as markers of Th1 cells. The aim of this study was to assess differential chemokine receptor expression from symptomatic atopic grass pollen-sensitive subjects, compared with patients on high-dose allergen injection immunotherapy (IT) and healthy controls. METHODS: We examined chemokine receptor expression (CCR1-7 and CXCR1-4) by flow cytometry of peripheral blood CD4+ and CD8+ T cells. We also depleted peripheral blood mononuclear cell (PBMC) populations of CCR3+ CD4+ cells by magnetic bead separation and cells were stimulated with grass pollen allergen for 6 days. Cytokine production was measured by enzyme-linked immunosorbent assay. RESULTS: On freshly isolated PBMC, atopic individuals exhibited increased numbers of CCR3+ CD4+ cells compared with normal controls (P < 0.01). CCR3 expression in IT patients was reduced compared with matched atopic rhinitic controls (P < 0.05) and comparable with that observed in normal subjects. Depletion of CCR3+ CD4+ cells from allergen-stimulated PBMC cultures resulted in decreased interleukin (IL)-5 production compared with whole CD4+ populations (P < 0.05). Freshly isolated CCR3+ CD4+ cells have significantly higher intracellular IL-4 and lower IFN-gamma levels than CCR3- CD4+ cells. CD4+ T cells cultured from both peripheral cells and nasal biopsies demonstrated increased expression of CCR3 in the presence of IL-4 (P < 0.05). CONCLUSION: CCR3+ CD4+ T cells are increased in allergic rhinitis, are reduced by allergen IT, have a Th2 phenotype and contribute to allergen-specific responses. Strategies against CCR3+ T cells may be effective in human allergic diseases.


Subject(s)
Desensitization, Immunologic , Receptors, Chemokine/metabolism , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Perennial/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Adult , Cell Count , Cells, Cultured , Female , Humans , Interleukin-5/metabolism , Leukocytes/metabolism , Male , Middle Aged , Poaceae/immunology , Receptors, CCR3 , Rhinitis, Allergic, Seasonal/immunology , Rhinitis, Allergic, Seasonal/metabolism , Th2 Cells/metabolism
11.
Eur Respir J ; 23(6): 876-84, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15219001

ABSTRACT

T-helper (Th) 2 cytokines are thought to mediate most features of allergic inflammation in atopic asthma. However, it remains unclear whether chemokine pathways direct selective recruitment of Th2 cells to the airways during human allergic responses. Bronchoalveolar lavage (BAL) was performed in 15 nonsmoking mild atopic asthmatics before and 24 h after a fibreoptic segmental allergen challenge, and chemokines related to T-cell recruitment were assayed by ELISA. The Th2-related C-C chemokine (CCR)4 ligands, macrophage-derived chemokine/C-C chemokine ligand (CCL)22 and thymus and activation-regulated chemokine/CCL17, were increased in BAL after challenge. These chemokines correlated significantly with lymphocyte numbers and with interleukin (IL)-5 and IL-13 in post-challenge BAL. In contrast, two out of three putative Th1-related chemokines did not change. There were no alterations in monokine induced by interferon (IFN)-gamma/CXC chemokine ligand (CXCL)9 or macrophage inflammatory protein-1alpha/CCL3; whereas a significant increase in IFN-induced protein-10kDa/CXCL10 was observed, which did not correlate with the T-cell influx. In peripheral mononuclear cells from atopic donors, CCL22 and CCL17 were induced by IL-4 and IL-13, further supporting the relationship between CCL22/CCL17 and Th2 cytokines. Finally, CCL22 was able to trigger actin polymerisation in peripheral CD4+ T-cells expressing CCR4. Thus, C-C chemokine receptor 4 ligands are up-regulated in the airways of atopic asthmatics following allergen exposure, contribute to the T-cell influx to the airways and are closely related to the Th2-cytokine response.


Subject(s)
Asthma/immunology , Receptors, Chemokine/metabolism , Th2 Cells/immunology , Adolescent , Adult , Bronchial Provocation Tests , Bronchoalveolar Lavage Fluid/cytology , Cell Count , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin E/blood , Male , Middle Aged , Receptors, CCR4 , Statistics, Nonparametric , Th2 Cells/metabolism , Up-Regulation
12.
Bull Math Biol ; 66(4): 791-808, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15210319

ABSTRACT

Shock waves have been proposed in the literature as a mechanism for retinal damage induced by ultra-short laser pulses. For a spherical absorber, we derive a set of linear equations describing the propagation of pressure waves. We show that the formation of shock fronts is due to the form of the absorber rather than the inclusion of nonlinear terms in the equations. The analytical technique used avoids the need for a Laplace transform approach and is easily applied to other absorber profiles. Our analysis suggests that the 'soft' nature of the membrane surrounding retinal melanosomes precludes shock waves as a mechanism for the retinal damage induced by ultra-short pulse lasers. The quantitative estimates of the pressure gradients induced by laser absorption which are made possible by this work, together with detailed meso-scale or molecular modelling, will allow alternative damage mechanisms to be identified.


Subject(s)
Lasers/adverse effects , Models, Biological , Retina/injuries , Humans , Melanosomes/radiation effects , Numerical Analysis, Computer-Assisted
13.
Bull Math Biol ; 65(4): 731-46, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12875340

ABSTRACT

We describe a new model for laser-induced retinal damage. Our treatment is prompted by the failure of the traditional approach to accurately describe the image size dependence of laser-induced retinal injuries and by a recently reported study which demonstrated that laser injuries to the retina might not appear for up to 48 h post exposure. We propose that at threshold a short-duration, laser-induced, temperature rise melts the membrane of the melanosomes found in the pigmented retinal epithelial cells. This results in the generation of free radicals which initiate a slow chain reaction. If more than a critical number of radicals are generated then cell death may occur at a time much later than the return of the retina to body temperature. We show that the equations consequent upon this mechanism result in a good fit to the recent image size data although more detailed experimental data for rate constants of elementary reactions is still required. This paper contributes to the current understanding of damage mechanisms in the retina and may facilitate the development of new treatments to mitigate laser injuries to the eye. The work will also help minimize the need for further animal experimentation to set laser eye safety standards.


Subject(s)
Lasers/adverse effects , Models, Biological , Retina/injuries , Eye Burns/etiology , Eye Burns/pathology , Free Radicals/adverse effects , Humans , Melanosomes/pathology , Pigment Epithelium of Eye/pathology , Temperature
14.
Clin Exp Immunol ; 132(1): 76-80, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12653839

ABSTRACT

Our objective was to characterize T-cell responses to Phleum pratense in grass pollen allergic individuals and healthy controls using the fluorescent dye PKH26. Peripheral blood mononuclear cells were stimulated with P. pratense, or with recall antigens, and CD3+/CD4+ and CD3+/CD8+ T-cells that had proliferated were analysed by flow cytometry. In the presence of P. pratense CD4+/CD3+ T-cells proliferated more in grass pollen sensitive atopic patients than in nonallergic controls or in nongrass pollen sensitive atopic subjects. PPD and TT recall antigens elicited uniformly high proliferation in all T-cell subsets. Only half of pollen sensitive patients also had an increased proliferation of CD3+/CD8+ T-cells in response to P. pratense. We determined precursor frequency of CD4+ T cells in the original population that responded to P. pratense and found values ranging from 1 x 10-3 to 0.6 x 10-1, in the same range as those measured for PPD and TT. In conclusion, grass pollen sensitive atopic patients show enhanced CD4+ T-cell reactivity to P. pratense, and this could be related to the presence of elevated numbers of circulating allergen-specific CD4+ T cells. This flow cytometric method should allow the identification of other phenotypic markers such as intracellular cytokines in allergen specific responding CD4+ T cells.


Subject(s)
Allergens/immunology , CD4-Positive T-Lymphocytes/immunology , Organic Chemicals , Phleum , Pollen/immunology , Rhinitis, Allergic, Seasonal/immunology , CD3 Complex , CD8-Positive T-Lymphocytes/immunology , Case-Control Studies , Cell Division , Flow Cytometry , Fluorescent Dyes , Humans , Lymphocyte Activation , Lymphocyte Count
15.
J Allergy Clin Immunol ; 108(2): 205-11, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11496235

ABSTRACT

BACKGROUND: Basophils represent an important source of inflammatory mediators and cytokines after IgE-dependent activation in human beings. OBJECTIVE: To assess the role of basophils in allergic asthma, we measured the number of basophils in the bronchial mucosa and their capacity to express IL-4 mRNA and protein during allergen-induced late asthmatic responses. METHODS: Fiberoptic bronchoscopic bronchial biopsies were obtained at 24 hours from sites of segmental bronchial allergen challenge and control sites in 19 patients with atopic asthma and 6 nonatopic healthy volunteers. Basophil numbers were assessed by immunohistochemistry through use of mAb 2D7. IL-4 mRNA--positive cells were detected through use of in situ hybridization and colocalized to basophils through use of sequential immunohistochemistry/in situ hybridization. IL-4 protein was detected and colocalized to basophils through use of dual immunohistochemistry. RESULTS: After allergen challenge, there was an increase in the median number of 2D7-positive basophils per square millimeter in the bronchial mucosa in patients with asthma (0.9 cells/mm(2) at baseline to 8.8 cells/mm(2) after challenge; P =.002), which also was significantly higher than what was seen in nonasthmatic controls (P =.01). Similarly, IL-4 mRNA--positive cells were increased at 24 hours in patients with asthma (1.4 to 14) in comparison with controls (0 to 0; P =.02). Colocalization studies revealed that 15% and 41% of the basophil population in patients with asthma after allergen-challenge expressed, respectively, IL-4 mRNA and protein. Conversely, 19% of IL-4 mRNA-positive cells and 72% of IL-4 protein--positive cells were accounted for by basophils. CONCLUSION: After allergen provocation in sensitive patients with atopic asthma, basophils are recruited to the bronchial mucosa and express IL-4 mRNA and protein, which might contribute to local IgE synthesis and/or tissue eosinophilia or other aspects of allergic inflammation during late responses and ongoing asthma.


Subject(s)
Asthma/immunology , Basophils/immunology , Interleukin-4/biosynthesis , Adult , Bronchi/immunology , Chemotaxis, Leukocyte , Female , Humans , Hypersensitivity, Immediate/immunology , Immunohistochemistry , In Situ Hybridization , Interleukin-4/genetics , Male , RNA, Messenger/isolation & purification , Respiratory Mucosa/immunology
16.
Allergy ; 56(2): 126-31, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11167372

ABSTRACT

BACKGROUND: Local antigen presentation may be necessary for both primary and recall T-cell responses to grass pollen in hay fever patients. We examined the effect of seasonal allergen exposure on nasal mucosal antigen-presenting cell (APC) populations and the effects of topical corticosteroid therapy. METHODS: Nasal biopsies were collected from 46 grass pollen-sensitive seasonal rhinitis patients before the grass-pollen season. A second biopsy was collected during the pollen season, when patients had received 6 weeks' treatment with either fluticasone propionate (200 microg, twice daily) or placebo. Cell populations in biopsy sections were quantified by immunocytochemistry. RESULTS: Significant increases in submucosal and epithelial CD1a+ Langerhans cells, but not CD68 + macrophages or CD20 + B cells, were observed during the pollen season. Seasonal increases in CD1a+ Langerhans cells were inhibited by corticosteroid therapy. CONCLUSIONS: Recruitment of CD1a+ Langerhans cells to the nasal mucosa during natural seasonal allergen exposure may contribute to local T cell responses. Topical corticosteroids may act, at least in part, by inhibiting effective allergen presentation to T cells through inhibition of recruitment of Langerhans cells to the nasal mucosa.


Subject(s)
Androstadienes/administration & dosage , Antigens, CD1/analysis , Langerhans Cells/physiology , Nasal Mucosa/immunology , Rhinitis, Allergic, Seasonal/drug therapy , Rhinitis, Allergic, Seasonal/immunology , Administration, Topical , Adult , Androstadienes/therapeutic use , Antigens, CD/analysis , Antigens, CD20/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Biopsy , Cell Movement/drug effects , Female , Fluticasone , Humans , Immunohistochemistry , Langerhans Cells/drug effects , Langerhans Cells/immunology , Macrophages/immunology , Macrophages/pathology , Male , Nasal Mucosa/pathology , Poaceae/immunology , Pollen/immunology
17.
Clin Exp Allergy ; 31(1): 69-76, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11167953

ABSTRACT

BACKGROUND: T-cell production of eosinophil-active cytokines (IL-5, IL-3, GM-CSF) is thought to be fundamental to asthma pathogenesis. Inhaled aeroallergens may be one important stimulus for T-cell cytokine production in asthma. OBJECTIVE: To compare the potency and efficacy of the topical anti-asthma glucocorticoids beclomethasone dipropionate (BDP) and fluticasone propionate (FP) in inhibiting allergen-driven peripheral blood T-cell proliferation and production of IL-3, IL-5 and GM-CSF mRNA and protein. METHODS: Peripheral blood mononuclear cells from six atopic asthmatics sensitized to house dust mite (HDM) were cultured in the presence of HDM and serial dilutions of BDP or FP in vitro. Cellular proliferation (7 days) and culture supernatant cytokine concentrations (6 days) were measured by uptake of tritiated thymidine and ELISA, respectively. Cytokine mRNA expression (24 h) was measured in three subjects using a quantitative PCR technique. RESULTS: Both BDP and FP inhibited allergen-induced T-cell proliferation, expression of IL-3, IL-5 and GM-CSF mRNA, and secretion of the corresponding proteins in a concentration-dependent fashion. FP was considerably more potent, but not more efficacious, in exerting these actions. CONCLUSIONS: Both BDP and FP have the potential markedly to inhibit allergen-induced T-cell production of asthma-relevant cytokines. This activity is effected at the level of T-cell proliferation and cytokine gene transcription. These properties may be key features of the anti-asthma activity of these drugs. The greater potency of FP in vitro may be responsible for its greater clinical potency.


Subject(s)
Androstadienes/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Asthma/drug therapy , Beclomethasone/therapeutic use , Cytokines/drug effects , Hypersensitivity, Immediate/drug therapy , Lymphocyte Activation/drug effects , Administration, Topical , Androstadienes/pharmacology , Anti-Inflammatory Agents/pharmacology , Antigens, Dermatophagoides , Asthma/immunology , Beclomethasone/pharmacology , Cytokines/metabolism , Dust/adverse effects , Fluticasone , Glucocorticoids , Glycoproteins/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Hypersensitivity, Immediate/immunology , Interleukin-3/metabolism , Interleukin-5/metabolism , Lymphocyte Activation/immunology , RNA, Messenger/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
18.
J Allergy Clin Immunol ; 106(5 Suppl): S221-6, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11080735

ABSTRACT

Recent evidence points to the recruitment of T(H)2 cells, phenotype T lymphocytes, their activation, and the generation of T(H)2 cytokines, particularly IL-4 and IL-5, in both peripheral blood and bronchial mucosa of asthmatic patients, leading to local tissue eosinophilia and IgE-dependent mast-cell activation. Activation of T(H)2 T lymphocytes appears to be specific for asthma (as opposed to airway obstructive disease) and was shown to correlate with asthma severity as evidenced by the inverse correlation between CD25(+)/CD4(+) cells and peak expiratory flow rates. These findings support the fundamental importance of T-lymphocyte responses in bronchial asthma and delineate potential therapeutic strategies, such as broad-based immunosuppression versus a more selective approach targeted against CD4(+) T lymphocytes. The high efficacy of topical treatments (ie, inhalation) supports the notion that changes that are detectable in peripheral blood merely reflect a "spill-over" of local T-lymphocyte responses in the target organ. Conversely, the multiple systemic manifestations of allergy (such as allergic rhinitis and atopic dermatitis in atopic patients) support systemic therapeutic approaches.


Subject(s)
Asthma/pathology , T-Lymphocytes/immunology , Animals , Asthma/blood , Bronchi/pathology , Humans , Interferon-gamma/blood , Interferon-gamma/metabolism , Interleukin-2/blood , Interleukin-2/metabolism , Interleukin-4/blood , Interleukin-4/metabolism , Interleukin-5/blood , Interleukin-5/metabolism , Mucous Membrane/immunology , Phenotype , Th1 Cells/metabolism , Th2 Cells/metabolism
19.
J Immunol ; 165(5): 2877-85, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-10946321

ABSTRACT

IL-12 suppresses proallergic Th2-type cytokine production and induces Th1-type cytokine production by peripheral blood T cells from subjects with allergic disease. The objective of the present study was to examine the relevance of these findings to target organ T cell responses in human asthma. Bronchoalveolar lavage (BAL) and PBMC were collected from atopic asthmatics 24 h after fiberoptic allergen challenge of a segmental bronchus. BAL T cells and PBMC were cultured with allergen in the presence of recombinant IL-12 or IFN-gamma, and cytokines were measured in culture supernatants after 6 days. IL-5 production by BAL T cells and PBMC was inhibited by IL-12 and, to a lesser extent, by IFN-gamma. IL-12 also induced IFN-gamma production by BAL T cells and PBMC. The effects of IL-12 nor IFN-gamma on IL-5 production could not be reversed by neutralizing anti-IFN-gamma or anti-IL-12 mAbs, respectively. Thus, the effect of neither IL-12 nor IFN-gamma appeared to be mediated through induction of the other cytokine. In situ hybridization revealed that approximately one-third of BAL T cells expressed mRNA transcripts encoding the IL-12R beta 2 subunit following allergen challenge. Thus, human T cells obtained from BAL during asthmatic late responses, like T cells in the peripheral circulation, remain susceptible to immunomodulation by IL-12. These findings raise the possibility that IL-12 may hold therapeutic potential in allergic diseases such as asthma.


Subject(s)
Allergens/administration & dosage , Asthma/immunology , Interleukin-12/pharmacology , RNA, Messenger/biosynthesis , Receptors, Interleukin/biosynthesis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Adult , Animals , Antibodies, Monoclonal/pharmacology , Asthma/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Clone Cells , Cytokines/biosynthesis , Cytokines/blood , Epitopes, T-Lymphocyte/immunology , Female , Humans , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interferon-gamma/pharmacology , Interleukin-12/metabolism , Interleukin-5/antagonists & inhibitors , Interleukin-5/biosynthesis , Interleukin-5/blood , Male , Mites/immunology , Pollen/immunology , Receptors, Interleukin/genetics , Receptors, Interleukin-12 , Time Factors
20.
J Allergy Clin Immunol ; 106(2): 293-301, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10932073

ABSTRACT

BACKGROUND: We have previously shown increased expression of the CD4(+) cell chemoattractant IL-16 in bronchial mucosa of patients with asthma. We investigated the effects of allergen challenge on airway IL-16 expression. METHODS: We investigated the expression of IL-16 immunoreactivity in bronchial biopsy samples obtained from atopic asthmatic subjects (n = 19) and normal subjects (n = 6) 24 hours after segmental allergen challenge. Control biopsy samples were obtained either at baseline or after diluent challenge. IL-16 expression was correlated to numbers of CD4(+) cells, CD25(+) cells, and activated eosinophils. IL-16 bioactivity was assessed in bronchoalveolar fluid obtained from patients with asthma. RESULTS: IL-16 expression was higher in control biopsy specimens obtained from subjects with asthma compared with normal subjects (P<.05). In patients with asthma, numbers of IL-16 immunoreactive cells were significantly higher in biopsy specimens obtained after allergen challenge compared with control biopsy specimens (P<.001). Allergen provocation was associated with release of IL-16 in bronchoalveolar fluid in patients with asthma. In normal subjects, there was no difference in the number of IL-16-immunoreactive cells in biopsy specimens obtained after allergen challenge compared with biopsy specimens obtained after diluent challenge. Allergen challenge was associated with an increase in the numbers of EG2(+) eosinophils in patients with asthma but not in normal subjects. IL-16 expression correlated with the numbers of CD4(+) cells and CD25(+) cells after allergen challenge in asthmatic subjects with a provocative concentration required to decrease the FEV(1) by 20% of its baseline value (PC(20)FEV(1)) < 4 mg/mL. IL-16-immunoreactive cells were identified mainly as T cells and eosinophils in asthmatic subjects after allergen challenge. CONCLUSION: Endobronchial allergen provocation in atopic asthmatic patients resulted in increased airway expression of IL-16 and release of bioactive IL-16 in airways. IL-16 may contribute to the immunoregulation of the inflammatory infiltrate in the airways in response to antigen.


Subject(s)
Allergens/pharmacology , Asthma/immunology , Interleukin-16/immunology , Adult , Bronchi , Bronchial Provocation Tests , Bronchoalveolar Lavage Fluid/chemistry , CD4-Positive T-Lymphocytes/cytology , Chemotactic Factors/metabolism , Eosinophils/chemistry , Female , Humans , Interleukin-16/genetics , Lymphocyte Count , Male , Phenotype , Receptors, Interleukin-2/analysis , Respiratory Mucosa/chemistry , Respiratory Mucosa/cytology , Respiratory Mucosa/immunology
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