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Biomedical subjects

A B Kay

Publications and source records attributed to A B Kay.

At least 199 records · Page 11Linked to original sources
PubMed1991

Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs.

OBJECTIVE: To evaluate the efficacy and safety of immunotherapy (hyposensitisation) in patients with severe summer hay fever. DESIGN: A randomised, double blind, placebo controlled study of a biologically standardised depot grass pollen extract. SETTING: Allergy clinic, Royal Brompton and National Heart Hospital, London. PATIENTS: 40 adults (mean age 35 years) with a history of severe grass pollen allergy uncontrolled by standard antiallergic drugs. Patients with perennial asthma were specifically excluded. INTERVENTION: Patients were randomised to receive either an active preparation (Alutard SQ, a grass pollen (Phleum pratense) extract) or placebo at a rate of two subcutaneous injections a week in increasing doses until a maintenance dose was reached. This maintenance dose was given once a month. MAIN OUTCOME MEASURES: Clinical efficacy was evaluated by symptom and drug diary cards, visual analogue scores during the grass pollen season, and a postseasonal assessment by the patients and a doctor. Conjunctival and skin sensitivity to local allergen provocation was measured before and after eight months of treatment. RESULTS: There was a highly significant decrease (median Alutard SQ v median placebo (95% confidence interval for difference between medians] in total symptom scores (p=0.001) in the Alutard SQ treated group (360 v 928 (238 to 825]. Significant differences were also found in total drug use (p=0.002, 129 v 627 (178 to 574]. Visual analogue symptom scores were also reduced in the active group (p=0.02, 2.2 v 5.5 (-4.8 to -0.5]. The postseasonal assessment, by either the doctor or the patients, showed a large improvement (p less than 0.001) in favour of Alutard SQ. Provocation tests showed a greater than 10-fold reduction for the active group in immediate conjunctival allergen sensitivity (p=0.001), a 40% decrease in early phase response (p=0.02), and a 57% decrease in the late phase (p=0.001) cutaneous response after intradermal allergen. A total of 523 active injections were given. There was one systemic reaction at 10 minutes after injection, which was rapidly reversed with intramuscular adrenaline. There was one mild delayed urticarial reaction at 2 1/2 hours. CONCLUSION: Immunotherapy is effective in patients with severe summer hay fever, but immediate anaphylactic reactions limit its use to specialised centres. Patient selection is extremely important, and chronic perennial asthma should be specifically excluded. As serious reactions occur within minutes a two hour wait for all patients after each injection seems unnecessary.

Adult↗
PubMed1991

Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness.

Bronchial biopsy specimens were obtained by fiberoptic bronchoscopy from 21 atopic subjects with asthma, 10 atopic subjects without asthma, and 12 normal healthy control subjects. With immunohistochemical techniques and a panel of monoclonal antibodies, inflammatory cells were identified and counted in the bronchial mucosa. The mean number of leukocytes (CD45+) and T-lymphocytes (CD3+, CD4+, and CD8+) at two airway levels in the subjects with asthma tended to be higher than in the other groups, but this difference did not achieve statistical significance. Similarly, there were no significant differences in the numbers of mucosal-type or connective tissue-type mast cells, elastase-positive neutrophils, or Leu-M3+ cells in the airway mucosa of subjects with asthma compared with atopic subjects without asthma and healthy control subjects. In contrast, significantly more interleukin-2 receptor-positive (CD25+) cells and "activated" (EG2+) eosinophils (EOSs) were present in the airways of subjects with asthma at both proximal and subsegmental biopsy sites. When the relationships between numbers of T-lymphocytes, activated (CD25+) cells, and EOSs were analyzed, there were positive correlations between CD3 and EG2, between CD3 and CD25, and between CD25 and EG2 positive cells in the airways of subjects with asthma. Furthermore, the ratio of EG2+ to CD45+ cells correlated with the provocative concentration of methacholine that caused a 20% decrease of FEV1 in hyperresponsive subjects. Although these associations do not prove a causal relationship, the results support the hypothesis that activated (CD25) T-lymphocytes release products which regulate recruitment of EOSs into the airway wall. In addition, our findings suggest that, in the large airways at least, asthma is not associated with hyperplasia of either mucosal-type or connective tissue-type mast cell.

Adult↗
PubMed1991

Immunotherapy and allergic inflammation.

A double-blind placebo-controlled trial of allergen injection immunotherapy in adult patients with severe summer hayfever. We used a partially purified biologically standardised grass pollen depot preparation (Alutard SQ, ALK Denmark Ltd.). Immunotherapy was extremely effective in reducing symptoms and medication requirements. Clinical improvement was accompanied by a decrease in both a target organ (conjunctival) and skin sensitivity. The injections were well-tolerated with minimal side effects. The results suggest that 30 minutes rather than 2 hours is an acceptable post-injection observation period. Successful immunotherapy was accompanied by suppression of the late cutaneous response to allergen. Specific immunostaining of skin biopsies revealed inhibition of the characteristic CD4+ T cell and EG2+ activated eosinophil cellular infiltrate during the late response. There was a significant relationship between CD4+ T cell and eosinophil counts after immunotherapy, i.e. the lower the number of infiltrating CD4+ cells, the lower the eosinophil counts. An unexpected finding was a prominent CD25+ (interleukin-2 receptor positive) cellular infiltrate which was only observed following Alutard SQ. Further studies involving double immunostaining methods should identify the phenotype of these activated, IL-2R+ cells. Based on murine studies Mosmann and colleagues have classified T cell responses into two types according to their profile of lymphokine production [11]. TH1 cells produce predominantly the IL-4 family of cytokines (IL-3, IL-4, IL-5) whereas TH2 cells produce predominantly interleukin-2 and interferon gamma. Insofar as the Mosmann classification may possibly be relevant to human T cell responses, the above findings would support a switch from a "TH2-" to a "TH1-" lymphocyte response following immunotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

TNF alpha mRNA expression in allergic inflammation.

Using the technique of in situ hybridization, we have attempted to identify messenger RNA for tumour necrosis factor-alpha (TNF alpha) in cells infiltrating allergen-induced late phase reaction (LPR) of the skin and the nose of atopic subjects. We have also compared the number of TNF alpha mRNA positive cells in bronchoalveolar lavage (BAL) from atopic asthmatics and normal controls. Twenty-four hours after local allergen challenge, 12/14 skin biopsies and 9/10 nasal biopsies had positive hybridization signals for TNF alpha mRNA whereas only 4/14 and 2/10 biopsies were positive in the relevant diluent controls. Compared with diluent sites significantly increased numbers of cells expressing mRNA for TNF alpha were observed in the LPR of skin (P less than 0.004) and nose (P less than 0.006). All BAL from asthmatics (n = 10) and from normal volunteers (n = 10) had cells showing positive hybridization signals for TNF alpha mRNA but these were at increased frequency in asthmatics (P less than 0.001). These results suggest that TNF alpha may be an important cytokine in atopic allergic inflammation.

Adolescent↗
PubMed1991

Failure to detect deposition of complement and immunoglobulin in allergen-induced late-phase skin reaction in atopic subjects.

There still remains some controversy regarding the possible role of immune complexes in the pathogenesis of the late-phase skin reaction (LPSR). To assess this, skin biopsies were obtained from LPSR induced in atopic human subjects 6, 24 and 48 h after allergen challenge. Cryostat sections were stained by direct immunofluorescence for the presence of fibrinogen, immunoglobulin classes IgM and IgG and for the complement components C1q and C3c. Complement components were observed in only two of the 29 biopsies studied. In both instances, only C3c was detected. One of these subjects also had unequivocal IgG staining at 6 h. IgM staining was detected in two out of 10 subjects at 6 h but no significant deposition of immunoglobulins could be found at 24 or 48 h. Fibrinogen deposition was observed in about half of the biopsies at each time-point. This study suggests that substantial complement and immunoglobulin deposition are not overt features of the allergen-induced LPSR, although the presence of small amounts of immune complexes, below the sensitivity of the method employed cannot be excluded. Fibrin deposition occurs in the LPSR but does not appear to be a prerequisite for LPSR development.

Allergens↗
PubMed1991

UCHL1+ (CD45RO+) 'memory' T cells predominate in the CD4+ cellular infiltrate associated with allergen-induced late-phase skin reactions in atopic subjects.

We have previously shown that CD4+ T lymphocytes accumulated at the site of allergen induced late-phase reactions (LPR) in the skin of atopic subjects. In order to determine whether these were predominantly 'memory' or 'naive' cells, monoclonal antibodies recognizing isoforms of the CD45 common leucocyte antigen and immunocytochemical methods were used to study the composition of the T cell infiltrate. Allergen-induced late-phase skin reactions were biopsied 6, 24 or 48 h after allergen challenge. Memory (CD45RO+/UCHL1+) T cells predominated and few naive (CD45RA+/Leu18+) cells were identified. Double immunofluorescence was used to confirm that the UCHL1+ and Leu 18+ cells were CD4+ T lymphocytes. The selective recruitment of memory T cells to LPR sites is consistent with the active involvement of T lymphocytes in atopic allergic inflammation. A possible alternative explanation for apparently selective recruitment is the differential expression of endothelial adhesion molecules on memory and naive T lymphocytes.

Antigens, Differentiation↗
PubMed1991

Immunohistology of human allergic late-phase skin reactions.

Human late-phase allergic skin reactions (LPSR) are characterised histologically by a mixed infiltrate of granulocytes and mononuclear cells. Quantitative immunohistology reveals a correlation between the numbers of CD4+ T-cells and the number of activated eosinophils at LPSR sites. These CD4+ T-cells are predominantly CD45RO+ and belong to the 'memory' T-cell subset. Immunofluorescence studies indicate that type III (immune complex) mechanisms make no significant contribution to the LPSR. On the other hand, the LPSR and classical delayed-type hypersensitivity (DHT) both have a marked CD4+ T-cell component. T-cell infiltration is a more diffuse process in DTH than in the LPSR; between 24 and 48 h, DTH sites show a further increase in T-cell numbers with the appearance of CD8+ T-cells and an influx of monocytes. Activated eosinophils are present in the early stages of both LPSR and DTH, but are more prominent in the LPSR. These different patterns of cellular infiltration and activation are probably due to differences in the cytokine secretion pattern of the infiltrating T-cells. Detailed analysis of this hypothesis will require the use of in situ hybridization techniques.

Eosinophils↗
PubMed1991

Interleukin-5 enhances the in vitro adhesion of human eosinophils, but not neutrophils, in a leucocyte integrin (CD11/18)-dependent manner.

Interleukin (IL-5) was found to enhance the adhesion of eosinophils, but not neutrophils, to both microvascular and large vein endothelial cells in a dose-dependent manner. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) and platelet-activating factor (PAF) enhanced both eosinophil and neutrophil adhesion. Significant increases in eosinophil CR3 expression, but not LFA-1, were observed following pre-incubation with PAF, IL-3, IL-5 or GM-CSF. Neutrophil CR3 expression was increased significantly by pre-incubation with PAF or GM-CSF, but not IL-3 or IL-5. Enhanced adhesion to human microvascular endothelial cells (HMVEC) or human umbilical vein endothelial cells (HUVEC) was inhibited by (ranked in order of potency) anti-CR3 alpha = common beta-chain greater than LFA-1 alpha. Anti-p150,95 alpha had no measurable effect. Basal expression of eosinophil CR3 with monoclonal antibody inhibited IL-5-induced eosinophil hyperadherence to HUVEC in a manner almost identical to inhibition in the presence of excess anti-CR3. Thus, a conformational or affinity change in adhesion receptors following activation seems more important than a simple increase in numbers. No inhibition of unstimulated eosinophil adhesion to HMVEC or HUVEC by CD11/18 monoclonal antibody was observed. These findings demonstrate that IL-5 enhances eosinophil, but not neutrophil, adherence reactions, by a mechanism dependent, at least in part, on the CD11/18 family of adhesion glycoproteins.

Antigens, CD↗
PubMed1991

T lymphocytes and their products in atopic allergy and asthma.

Various cells are associated with inflammatory events characteristic of atopic allergy and asthma. As well as T cells and eosinophils, mast cells, basophils, mononuclear phagocytes and platelets have all to be considered particularly as their mediators have potential for contributing directly to the features of bronchial asthma. Nevertheless, mast cell/T lymphocyte/eosinophil interactions may be of particular significance. For instance, the acute symptoms of allergy and asthma such as sneezing, bronchospasm and hives are believed to be largely the result of mediator release from mast cells whereas chronic symptoms (the result of allergic inflammation) can be explained on the basis of eosinophil-mediated tissue damage. Allergen is recognized directly by T cells. Specialized T cell subsets, possibly the Th2 equivalent, predominate in allergy and elaborate IL-4 (an essential co-factor for IgE production) and IL-5 which brings about terminal differentiation and activation of the eosinophil. Basic proteins derived from the crystalloid granule together with PAF and leukotrienes produce chronic wheeze, bronchial irritability, and might also be involved in permanent nasal blockage in chronic rhinitis. This general hypothesis is continually being tested. It is clearly important to identify precise molecular targets in allergy and asthma in order to construct therapeutic strategies.

Asthma↗
PubMed1991

CD4 T lymphocyte activation in acute severe asthma.

The expression of activation molecules on peripheral-blood CD4 and CD8 T lymphocytes and the serum concentrations of two products of activated T lymphocytes [interferon-gamma (IFN-gamma) and soluble interleukin-2 receptor (sIL-2R)] were measured in patients with acute severe asthma (ASA) and controls. Significantly higher percentages of CD4+ cells from patients with ASA expressed IL-2R, HLA-DR and VLA-1 as compared to controls (p less than 0.01). In contrast, CD8+ cells from both asthmatics and controls did not express IL-2R and VLA-1, and their expression of HLA-DR in asthmatics was not increased. Serum concentrations of IFN-gamma and sIL-2R were significantly elevated in patients with ASA as compared to control groups (p less than 0.01). Concentrations decreased as the patients improved clinically following therapy. Significant correlations were observed between the improvements in airways obstruction and (1) the decreases in the percentages of peripheral-blood IL-2R+ T lymphocytes and (2) the decreases in serum concentrations of sIL-2R. These observations suggest that CD4 T lymphocyte activation is important in the pathogenesis of ASA.

Acute Disease↗
PubMed1991

Effects of cetirizine on human eosinophil and neutrophil activation in vitro.

The ability of cetirizine, a novel antihistamine agent, to inhibit the in vivo activation of human eosinophils, neutrophils and monocytes has been investigated using C3b- and IgG-dependent rosette formation, cytotoxicity against opsonised parasitic larvae and adherence to plasma-coated glass (PCG). The drug inhibited platelet-activating factor (PAF)-induced enhancement of eosinophil and neutrophil IgG (Fc) and complement (C3b) rosettes with an IC50 of 2 x 10(-5) M. There was also comparable inhibition of PAF-dependent enhancement of eosinophil cytotoxicity (for complement-coated schistosomula of Schistosoma mansoni). Cetirizine inhibited PAF-induced eosinophil, but not neutrophil, hyperadherence to PCG. These data support the view that cetirizine may exert some of its anti-allergic effects by inhibiting the activation of human granulocytes and that it may also selectively inhibit PAF-induced eosinophil hyperadherence.

Animals↗
PubMed1991

Cultured peripheral blood mononuclear cells derived from patients with acute severe asthma ("status asthmaticus") spontaneously elaborate a neutrophil chemotactic activity distinct from interleukin-8.

Peripheral blood mononuclear cells (PBMC) isolated from patients with acute severe asthma on the day of admission to hospital were cultured in vitro in serum-free medium in the absence of mitogenic stimulants for as long as 72 h. PBMC isolated from control groups (mild asthma, chronic obstructive airway disease, normal subjects) were cultured in a similar fashion. After incubation, the culture supernatants were tested for neutrophil chemotactic activity (NCA) using a modified Boyden chamber technique. PBMC from patients with acute severe asthma elaborated significantly greater amounts of NCA into the culture supernatants as compared with all three control groups (p less than 0.01). The amounts of PBMC-derived NCA from the same patients after 7 days of hospital therapy and clinical improvement were reduced (p less than 0.01). A correlation was observed between the extent of reduction in spontaneous release of NCA by PBMC derived from patients with acute severe asthma and the degree of clinical improvement of their asthma (p less than 0.02). Both monocytes and lymphocytes, when cultured separately, released NCA in amounts sufficient to account for the total activity released by unfractionated PBMC. NCA in PBMC culture supernatants accumulated progressively with time, a process inhibited in a dose-dependent fashion by cycloheximide. The amounts of NCA in culture supernatants did not correlate with the concentrations of histamine in lysates of the PBMC prepared just prior to culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗