Search PubMed⌕ Search

Biomedical subjects

A J Frew

Publications and source records attributed to A J Frew.

At least 109 records · Page 6Linked to original sources
PubMed1991

Eosinophil activation and T lymphocyte infiltration in allergen-induced late phase skin reactions and classical delayed-type hypersensitivity.

T lymphocyte infiltration is a well documented feature of classical delayed-type hypersensitivity (DTH) reactions. Recently, we have shown that T lymphocytes and activated (EG2+) eosinophils accumulate in the allergen-induced late phase skin reaction (LPR). To compare the kinetics and phenotypic composition of these T lymphocyte responses, LPR and DTH reactions of comparable induration size were induced in atopic subjects. In addition, DTH and LPR were compared between atopic and nonatopic subjects. In atopic individuals, allergen challenge elicited a perivascular influx of T lymphocytes that was predominantly CD4+. Eosinophil accumulation and activation were also prominent. There was no cellular response to allergen challenge in the nonatropic group. In both groups, DTH responses showed an intense T cell infiltrate which was more dense and dispersed than in the LPR. CD4+ T cells predominated but at 48 h CD8+ numbers were also significantly increased. In DTH, total leukocyte numbers (CD45+) were increasing at 48 h, whereas in the LPR, cell numbers reached a plateau between 24 and 48 h. T cell activation (shown by expression of IL-2R) was more prominent in DTH. Endothelial expression of HLA-DR was increased in both LPR and DTH, implying the local release of inflammatory cytokines in both reactions. Small but significant numbers of activated eosinophils (EG2+) were detected in atopics and non-atopics at 24 h in DTH but not at 48 h. These findings suggest that the allergen-induced LPR induced in atopic subjects is, at least in part, a form of cell-mediated hypersensitivity but with T cell kinetics that differ from classical DTH.

Adolescent↗
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

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

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

Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro.

A total of 37 chronic, severe, nonsmoking asthmatic patients with documented reversible airways obstruction were classified as glucocorticoid-sensitive or -resistant on the basis of changes in FEV1, FVC, and peak expiratory flow (PEF) after oral prednisolone. The resistant patients showed no significant improvements in airflow limitation. Phytohemagglutinin (PHA)-induced proliferation of peripheral blood T lymphocytes from the sensitive but not the resistant asthmatic patients was significantly (p less than 0.01) inhibited by dexamethasone (10(-7) mol/L), reflecting a shift of the dose-response curve. When all the asthmatic patients were analyzed together, there was a significant correlation between the degree of sensitivity of T cells to dexamethasone and the clinical responsiveness to prednisolone (p less than 0.01). No differences were observed between six of the sensitive and resistant patients in the clearance of plasma prednisolone derived from orally administered prednisone. Peripheral blood mononuclear cell glucocorticoid receptors were also characterized in five sensitive and seven resistant patients. The numbers and binding affinities of these receptors could not account for the observed difference in the susceptibility of these cells to functional inhibition by dexamethasone in vitro. These results suggest that clinical glucocorticoid resistance in chronic asthma does not reflect abnormal glucocorticoid clearance but may be due at least partly to a relative insensitivity of T lymphocytes to glucocorticoids. This lack of sensitivity is unexplained but is not attributable to abnormalities of cellular glucocorticoid receptors.

Adult↗
PubMed1991

Glucocorticoid resistance in chronic asthma. Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A.

A total of 37 chronic severe asthmatic patients with documented reversible airways obstruction were classified as glucocorticoid sensitive or resistant according to changes in the FEV1 following a course of oral prednisolone. The phenotype and expression of activation molecules on peripheral blood T lymphocytes from these patients just before the course of prednisolone were studied using flow cytometry. The resistant patients had significantly elevated percentages of T lymphocytes expressing the activation molecules IL-2R and HLA-DR compared to the sensitive patients. There were no differences between the patient groups in the percentages of peripheral blood T lymphocytes expressing the phenotypic markers CD4 and CD8. Peripheral blood mononuclear cells (PBMC) from 29 patients were cultured in vitro with the T lymphocyte mitogen PHA in the presence or absence of dexamethasone or cyclosporin A. Dexamethasone (10(-7) mol/L) significantly inhibited the proliferation of T lymphocytes from the sensitive but not the resistant asthmatic subjects. In contrast, cyclosporin A (500 ng/ml) inhibited proliferation of T lymphocytes from both the sensitive and the resistant asthmatic subjects, although the effect was less marked in the latter group. Inhibition of elaboration of interleukin-2 and interferon-gamma by mitogen-stimulated T lymphocytes from sensitive and resistant asthmatic patients was also studied. Dexamethasone (10(-7) mol/L) significantly inhibited the production of interleukin-2 and interferon-gamma by proliferating T lymphocytes isolated from the glucocorticoid-sensitive but not the resistant chronic asthmatic patients. Cyclosporin A (500 ng/ml) inhibited the elaboration of both lymphokines by T lymphocytes derived from both patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The role of cellular immunology in asthma.

It is now clear how activated T lymphocytes, through the elaboration of proinflammatory lymphokines, may orchestrate the inflammatory response seen in the asthmatic bronchial mucosa. This activation presumably follows recognition of specific antigen by the T lymphocytes. What is the nature of the putative activating antigen(s) in asthma? They might originate from an external source. Viral respiratory infections may be responsible for some exacerbations of asthma and may even initiate persistent airways obstruction, but it is unlikely that they can be implicated in every case. Aeroallergens are other obvious candidates, although it has already been argued that the atopic phenotype is not a prerequisite for the development of asthma, nor does atopy inevitably result in the development of airways hyperresponsiveness. An attractive alternative hypothesis is that the T lymphocytes may be inappropriately recognizing antigens in the bronchial mucosa; in other words asthma may be an "autoimmune" disease. An analysis of possible selective clonal expansion of T lymphocytes at the mucosal surface may provide evidence for a localized response against a limited range of antigens. It will be of particular importance to determine the amount and proportions of lymphokines secreted by T lymphocytes within the mucosal microenvironment, since properties of cells in the peripheral blood or even bronchoalveolar lavage (BAL) fluid are likely to reflect only dimly those of cells at this site. Furthermore, there is now good evidence that diapedesis of lymphocytes from the circulation to mucosal surfaces is a selective process mediated through specific "addressing" molecules on high endothelial venules at these sites. One example of such a molecule is that recognized by the monoclonal antibody Hermes-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1990

T lymphocytes and eosinophils in allergen-induced late-phase asthmatic reactions in the guinea pig.

The kinetics and phenotype of T lymphocytes infiltrating the airways of guinea pigs undergoing late-phase asthmatic reactions (LAR) were studied with monoclonal antibodies, cytofluorimetry, and immunocytochemistry. Challenge of sensitized animals with aerosolized ovalbumin was followed by early (2 h) and late-phase (17 h) bronchoconstriction. The induction of hypersensitivity, by aerosolized antigen, was associated with an increase in mucosal T cell numbers, which consisted almost entirely of CD8+ T cells. Following allergen challenge of fully sensitized animals, a biphasic rise in total T cell (CD3+) numbers was observed in the bronchial mucosa, peaking at 17 and 48 h. A similar pattern of T cell accumulation was observed in the bronchial adventitia but with an extra early peak at 2 h. In contrast to the T cell influx of the sensitization phase, the postchallenge infiltrate consisted largely of CD3+, CD8- cells. Eosinophil numbers were elevated in both submucosa and adventitia, with a single broad peak between 17 and 48 h. T cell infiltration was compared with eosinophil accumulation; while correlations between T cell and eosinophil numbers varied over the 96 h of the experiment, strong associations were observed between CD8+ numbers and eosinophils in the adventitia at 6 h (r = 0.733, p less than 0.01) and between CD3+ numbers and eosinophils in the submucosa at 72 h (r = 0.88, p less than 0.001). No significant changes were detected in T cell or eosinophil numbers in the lung parenchyma. There was a postchallenge increase in eosinophils (but not T cells) in bronchoalveolar lavage (BAL).(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1990

Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma.

We have used immunohistochemistry and monoclonal antibodies to analyze the phenotypic composition and activation status of the cellular infiltrate of bronchial biopsies obtained by fiber optic bronchoscopy of 11 atopic asthmatic subjects (FEV1% predicted range 78 to 114), 9 atopic nonasthmatic control subjects, and 10 normal healthy subjects. Examination of mucosal biopsies obtained from both central (level I) and subsegmental (level II) bronchi showed that the highest number of CD45-, DC3-, DC4-, and CD8-positive cells were found in the group with asthma. There was a significant increase in the number of interleukin-2 receptor (CD25)-positive cells (a marker of lymphocyte activation) at airway level I in the asthmatic group compared with both nonasthmatic atopic (p less than 0.05) and normal control subjects (p less than 0.01). Eosinophil numbers were significantly increased in asthma at both airway levels and at airway level II in the nonasthmatic atopic group when compared with normal healthy control subjects (p less than 0.05). EG2-positive cells (an index of secretion of eosinophil cationic protein following activation) were found at both airway levels in the asthmatic group and at level I in the nonasthmatic atopic control group (p less than 0.05). When asthmatic subjects were compared with normal healthy subjects, there was a reduction in the number of neutrophil elastase-positive cells in the asthmatic subjects which, as a percentage of leukocytes, was significant (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Breathing muscle activity during expiration in patients with chronic airflow obstruction.

During quiet ventilation in 10 patients with severe chronic airflow obstruction (AFO) there were large tidal swings of pleural pressure, 15.8 +/- 5.1 cmH2O, with high negative pressures achieved, 15.2 +/- 5.2 cmH2O. The pattern of pleural pressure mirrored that of tidal expiratory flow with a rapid rise to maximum of pleural pressure and flow at the beginning of expiration, a slow decline of both throughout most of expiration, and just before the onset of inspiration at flow reversal, a sharp fall in pleural pressure and expiratory flow. The shape of expiratory flow and pleural pressure tracings and the pattern of EMG recordings are compatible with loss of post-inspiratory muscle braking of flow. The generally negative pleural pressure and the EMG silence during expiration indicated relaxation of expiratory muscles throughout expiration. Extrapolation of the tidal expiratory flow curve to zero, and calculation of the area under the extrapolated curve showed the volume of dynamic hyperinflation to be a small proportion of the total increase in functional residual capacity above the predicted value in these patients.

Adult↗
PubMed1989

T lymphocytes in allergen-induced late-phase reactions and asthma.

We have studied a number of aspects of the interrelationship between T lymphocytes and allergic inflammation. Using monoclonal antibodies and immunocytochemistry we have observed significant infiltration by CD3+/CD4+ T lymphocytes together with evidence of T cell activation in the allergen-induced late-phase skin reaction in human atopic subjects. These changes were accompanied by eosinophil infiltration and activation. Activated T cells were also detected in the blood of patients with acute severe asthma. The role of T lymphocytes in granulocyte chemotaxis and activation was also explored, using recombinant human lymphokines, and we have identified and characterized two lymphokines which have specific effects upon neutrophils.

Acute Disease↗
PubMed1989

The activated eosinophil in allergy and asthma.

Our studies indicate that human eosinophils can be activated in terms of up-regulation of surface receptors, increased membrane lipid generation, and enhanced cytotoxicity by a variety of pharmacological mediators, through IgE-, IgG-, and complement-dependent pathways. PAF is an impressive activator of eosinophil function and is the most potent chemotactic mediator for eosinophils so far described. It is not selective in that neutrophils are also attracted by PAF. In our hands, IL-1, IL-2, granulocyte/macrophage-colony stimulating factor, tumor necrosis factor, interferon-gamma, and IL-5 tested over a wide concentration range gave very weak chemotaxis for eosinophils in vitro. Nevertheless, in vivo infiltration of eosinophils into the site of allergic tissue reactions is closely associated with the local accumulation of activated (CD4+, IL-2 rec+) T cells. We suggest, therefore, that the selective eosinophil infiltration seen in allergic inflammation may result from the initial recruitment and activation of granulocytes by lipid mediators and the subsequent selective activation of eosinophils by cytokines.

Asthma↗
PubMed1988

The relationship between infiltrating CD4+ lymphocytes, activated eosinophils, and the magnitude of the allergen-induced late phase cutaneous reaction in man.

The phenotype and activation status of leukocytes infiltrating human late phase allergic skin reactions were investigated by immunocytochemistry using a panel of mAb. Late phase skin reactions were induced in atopic individuals by intradermal challenge with allergen extract (grass pollen or house dust mite) and skin biopsies were obtained 6, 24, or 48 h after challenge. Cryostat sections were examined for evidence of infiltration and activation of T cells and eosinophils. Biopsies from saline-challenged control sites were used for comparison. A substantial number of CD3+ cells were observed close to the dermal capillaries. The number of CD4+ cells showed a similar pattern but few CD8+ cells were seen. The ratio of CD4 and CD8 subsets in tissue did not relate to the CD4/CD8 ratio in the peripheral blood. Two observations suggested that T cells had become activated: first, a small number of infiltrating cells bore receptors for IL-2, and second, there was indirect evidence of IFN-gamma secretion, demonstrated by increased expression of HLA-DR on endothelial cells and de novo expression of CD4 Ag on epidermal Langerhans cells. Activated eosinophils were detected in most of the allergen-challenged biopsies. The late phase reaction diameter at 6 h correlated with the number of activated eosinophils at 48 h (r = 0.61, p = 0.05), but not with infiltration by T cells. There was a strong correlation between the numbers of CD4+ cells and activated eosinophils at 24 h (r = 0.94, p less than 0.001). These findings suggest that interactions between T lymphocytes and eosinophils in reactions to airborne allergens may be more important than has previously been recognized.

Adolescent↗
PubMed1988

Empyema and mesangiocapillary glomerulonephritis with nephrotic syndrome.

Two cases of empyema with nephrotic syndrome are described, a previously unreported association. In one case the nephrotic syndrome resolved with treatment of the empyema. Renal biopsy in both patients showed mesangiocapillary glomerulonephritis and in one case there was evidence of activation of the alternative complement pathway, which is often associated with this histological type of glomerulonephritis. The association between glomerulonephritis and empyema is important because it represents a potentially reversible form of renal disease.

Adult↗