Eosinophils In Mucosa Research Articles

Mucosal inflammation in severe glucocorticoid-dependent asthma.

To improve our understanding of the inflammatory mechanisms underlying severe disease, a biopsy study was performed comparing 15 clinically unstable glucocorticoid-dependent asthmatics, 10 mild asthmatics, and 10 control subjects. Compared with mild asthma, severe asthma was characterized by reduced mucosal eosinophilia. Whilst no significant differences were found in the numbers of mast cells, neutrophils, CD3+ and CD4+ T-cells between the three groups, up to a 4-fold increase In the numbers of activated T-lymphocytes bearing the interleukin (IL)-2 receptor (IL-2R) was found in the mucosa in severe asthma compared to mild asthma (p = 0.03) and control subjects (p = 0.003). Compared to control subjects, the mucosa of severe asthmatics contained significantly (p = 0.02) higher numbers of IL-5+ cells, with no differences between mild and severe disease. In contrast, staining for the anti-IL-4 monoclonal antibody 3H4 revealed that biopsies from mild asthmatics contained more IL4+ cells than biopsies from severe asthmatics and control subjects (p = 0.0008). In the severe asthmatics, a close correlation (r(s) = 0.76, p = 0.005) was found between the numbers of IL-2R-bearing cells and the variability in peak expiratory flow. In conclusion, persistent T-cell activation is a prominent feature of severe asthma. These results also indicate that interleukin-5, and not interleukin-4, is upregulated in severe disease.

ABNORMAL ORO-ANAL TRANSIT IN ATOPIC MEDIATED REFRACTORY CONSTIPATION

104 Constipation may occur in as many of 40% of atopic children but the role of atopy in intractable constipation and the underlying motor disorder is unexplained. We prospectively studied 30 consecutive children with intractable constipation (11 male, 9 female) in whom "physical" cause had been excluded. 14/30 were atopic, 11/14 were intolerant of cows milk and 2/14 wheat. Dietary restriction resulted in normal bowel habit in 11/14 children. The remaining 3 non-responders, 2/3 responded to a dietary restriction of wheat. Similar attempts at dietary restriction showed no effect in non-atopic age and sex matched controls. In 16/30 non-atopic controls non-atopic controls dietary restriction had no effect. Radiopaque pellets transit studies in 8/14 showed normal transit but retention in the rectum before dietary restriction and clearance after restriction. Eosinophilic infiltration of the lamina propria was present in 7/7 children biopsied. Inhibition of the ano-rectal reflex was studied on 28 occasions in 5 patients by anorectal manometry and was no different to controls but interval anal sphincter control was elevated in the atopic group; 25-44 Vs controls 20,18-22 mmHg median and range p<0.03. We conclude refractory constipation in atopic children is commonly associated with mucosal eosinophilia, normal oro-rectal but delayed oro-anal transit with recto-anal hold up of the stool passage. Dietary manipulation should be an integral part of the treatment of children with atopy and intractable constipation.

CLINICAL RESPONSE TO AMINO ACID-BASED ENTERAL FORMULA IN NEUROLOGICALLY IMPAIRED CHILDREN WITH REFRACTORY ESOPHAGITIS

68 Recent results indicate that chronic gastrointestinal symptoms and histological changes of gastroesophageal reflux disease (GERD) unresponsive to standard treatments can be improved by the use of elemental formulas. GERD is common in neurologically impaired children (NIC), and the disorder is notoriously resistant to both medical and surgical treatments in this subject group. Because of prior observations in normally developed children, this investigation was designed to determine the efficacy of a dietary trial with an elemental formula on GERD in NIC who had not responded to medical and/or surgical therapy. Eight children (mean age ±SD: 53.7 ±40.9 months; 6 females) affected by cerebral palsy and having severe mental retardation were studied. Each had a long-standing history of GERD that had persisted despite standard antireflux therapies, including omeprazole in all and Nissen fundoplication in 3. The diagnosis of GERD was based on presence of typical microscopic changes of the esophageal mucosa. Subjects were fed the amino acid-based elemental formula Neocate (Nutricia) by mouth or by nasogastric tube for a minimum of 4 weeks while prior stable treatments for reflux disease were continued. Each child underwent endoscopy with esophageal biopsies and a cellobiose/mannitol sugar permeability test before and after the dietary trial. Symptomatology, endoscopy, and histology were graded using scales reflecting increasing severity with increasing grade; histology was graded by an observer who was blinded to the endoscopic findings. RESULTS: Using conventional histological criteria, esophagitis was considered moderate in 7 and mild in 1 at the beginning of the dietary trial. Five (62.5%) of the 8 patients also had an abnormal sugar permeability test, but none had an allergy history or positive skin testing to food antigens. By the end of the dietary trial, 7 of the 8 patients (87.5%) became free of their long-term complaints (regurgitation and/or vomiting, abdominal pain, chronic pulmonary aspiration). Furthermore, both endoscopic and histological findings of GERD significantly improved (p<0.01 and p<0.05, respectively using Fisher's exact test). Nevertheless, no significant changes were found in the number of esophageal mucosal eosinophils and mast-cells. After the trial, the permeability sugar test normalized in 3 of the 5 (60%) with initially abnormal studies. CONCLUSIONS: A course of a highly restricted diet with an amino acid-based formula may reverse long-standing upper gastrointestinal symptoms and resolve esophagitis in NIC who are unresponsive to conventional antireflux treatment. The mechanisms responsible for symptom and histological improvement remain uncertain, but they are not necessarily immunologic in nature. Disclosure: The authors have no financial interest in the described products.

Allergen challenge‐induced acute exudation of IL‐8, ECP and α2‐macroglobulin in human rhinovirus‐induced common colds

Rhinovirus infections cause exacerbations of eosinophilic airway disease. The acute effects of allergen‐challenge on nasal interleukin‐8 (IL‐8), eosinophil cationic protein (ECP), and α2‐macroglobulin were examined in atopic subjects with common cold symptoms.Twenty‐three patients with seasonal allergic rhinitis were inoculated with human rhinovirus 16 outside the pollen season. Diluent and allergen challenges, followed by nasal lavages, were carried out about 3 months before and 4 days after virus inoculation.Seventeen patients developed significant common cold symptoms with increased nasal lavage fluid levels of α2‐macroglobulin, IL‐8, and ECP at baseline (p<0.001–0.05 versus before inoculation), and were further increased by allergen challenge (p<0.001–0.05); IL‐8 and ECP levels were correlated (r=0.63, p<0.001). Before inoculation, the six patients who later did not develop common cold symptoms had high levels of IL‐8 and myeloperoxidase (MPO), and exhibited strong allergen‐induced plasma exudation responses (α2‐macroglobulin). After inoculation, IL‐8 and ECP did not increase in these symptomless subjects.In conclusion, high nasal interleukin‐8 and myeloperoxidase levels and exudative hyperresponsiveness may protect against infection. The association between nasal interleukin‐8 and eosinophil cationic protein in common cold, particularly that observed in nasal lavage fluids after allergen‐induced acute exudation of plasma, suggests the involvement of interleukin‐8 in exacerbation of airway mucosal eosinophil activity.

Allergen challenge-induced acute exudation of IL-8, ECP and alpha2-macroglobulin in human rhinovirus-induced common colds.

Rhinovirus infections cause exacerbations of eosinophilic airway disease. The acute effects of allergen-challenge on nasal interleukin-8 (IL-8), eosinophil cationic protein (ECP), and alpha2-macroglobulin were examined in atopic subjects with common cold symptoms. Twenty-three patients with seasonal allergic rhinitis were inoculated with human rhinovirus 16 outside the pollen season. Diluent and allergen challenges, followed by nasal lavages, were carried out about 3 months before and 4 days after virus inoculation. Seventeen patients developed significant common cold symptoms with increased nasal lavage fluid levels of alpha2-macroglobulin, IL-8, and ECP at baseline (p<0.001-0.05 versus before inoculation), and were further increased by allergen challenge (p< 0.001-0.05); IL-8 and ECP levels were correlated (r = 0.63, p<0.001). Before inoculation, the six patients who later did not develop common cold symptoms had high levels of IL-8 and myeloperoxidase (MPO), and exhibited strong allergen-induced plasma exudation responses (alpha2-macroglobulin). After inoculation, IL-8 and ECP did not increase in these symptomless subjects. In conclusion, high nasal interleukin-8 and myeloperoxidase levels and exudative hyperresponsiveness may protect against infection. The association between nasal interleukin-8 and eosinophil cationic protein in common cold, particularly that observed in nasal lavage fluids after allergen-induced acute exudation of plasma, suggests the involvement of interleukin-8 in exacerbation of airway mucosal eosinophil activity.

TACROLIMUS (FK506) INDUCED COLITIS IN PEDIATRIC LIVER TRANSPLANT (OLT) RECIPIENTS. IS IT ALLERGIC IN NATURE?

108 FK506 is a macrolide immunosuppressive that is increasingly being used for prevention of graft rejection in transplant recipients. It shares similar toxicity profiles with cyclosporine (CSA). However, very little is reported about its GI side effects. We retrospectively identified 3 patients who were started on FK506 post OLT and developed biopsy proven colitis, thought to be allergic in nature. Case 1 underwent OLT after a failed Kasai procedure for biliary atresia; 20 mos later, he developed guaiac positive diarrhea, neg for pathogens. Colonoscopy revealed focal colitis. He was also noted to have peripheral eosinophilia (24%) and positive RAST for milk protein. CSA was substituted for FK506 with resolution of symptoms on a milk restricted diet. Case 2 received OLT for Alagille syndrome at 33 mos of age (CSA primary therapy). FK506 was started a month later for mild rejection. He developed diarrhea 23 mos later, negative for pathogens. Flexible sigmoidoscopy revealed active as well as chronic inflammation. He had mild eosinophilia but normal IgE levels. A month later he developed PTLD along with marked eosinophilia (32%) and was switched to CSA as well as a milk restricted diet with resolution of symptoms. Case 3 underwent OLT for fulminant hepatic failure of unknown etiology, followed 4 mos later by BMT for aplastic anemia. 17 mos after OLT, he developed guaiac positive diarrhea, negative for pathogens. Peripheral eosinophilia (∼9%) was also found. Colonoscopy revealed increased mucosal eosinophils without activity or evidence of GVHD. RASTs were positive for milk, wheat, eggs, and oats. He was placed on a restricted diet but persistence of symptoms necessitated switch to CSA with subsequent resolution of symptoms. Conclusions: In these patients, FK506 was associated with the induction of allergic colitis. Therapy was facilitated by discontinuation of FK506 and switch to CSA. More studies are needed in a controlled setting to identify the prevalence of similar findings among pediatric liver transplant recipients.

Cytolysis and piecemeal degranulation as distinct modes of activation of airway mucosal eosinophils

Background: Cytotoxic eosinophil granule proteins are considered important in the pathogenesis of inflammatory airway diseases, including asthma, rhinitis, and polyposis. However, little is known about the mechanisms involved in the deposition of these tissue-damaging granular products in vivo. Objective: We sought to determine the occurrence of degranulating eosinophils, those with morphologic evidence of cytolysis with associated clusters of free eosinophil granules (Cfegs), and to identify the frequency of apoptotic eosinophils in inflamed upper airway tissue. Methods: Eosinophil-rich nasal polyps were processed for transmission electron microscopy and for light microscopic evaluation of whole-mount preparations subjected to deep tissue staining for eosinophil peroxidase. Results: The mean proportion of eosinophil subtypes were intact and resting (6.8%), intact but degranulating (83%), cytolytic or Cfegs (9.9%), and apoptotic (0.0%). All degranulating eosinophils exhibited piecemeal degranulation. The occurrence of Cfegs was confirmed in nonsectioned whole-mount preparations. Depending on the appearance of their core and matrix, the specific granules were divided into four subtypes, and a degranulation index (altered per total granules) was calculated for each eosinophil. Cytolytic eosinophils had a much lower degranulation index than intact eosinophils present in the same tissue ( P < .001). Conclusions: These data indicate that eosinophil cytolysis is present in human airway mucosa, that its occurrence is not an artifact of the means of tissue handling, and that cytolysis of eosinophils may occur without prior extensive degranulation. We suggest that eosinophil cytolysis is a major activation mechanism, which occurs along with, but is distinct from, other types of degranulation. (J Allergy Clin Immunol 1998;102:286-94.)

A murine model of allergic rhinitis: Studies on the role of IgE in pathogenesis and analysis of the eosinophil influx elicited by allergen and eotaxin

Background: Allergic rhinitis is a prevalent disease with significant morbidity. Studies of its pathophysiology in human subjects have been limited. Nasal biopsy specimens are difficult to obtain, and nasal secretions incompletely reflect the cellular and molecular events in the mucosa. IgE-mediated mast cell activation and the elaboration of factors promoting eosinophil development and chemotaxis are likely to participate in pathogenesis. Objectives: We sought to develop a murine model of allergic rhinitis, to use it to assess the role of IgE in pathogenesis, and to study the effects of IL-5 and eotaxin in the nasal mucosa. Methods: A protein extract of Aspergillus fumigatus ( Af) was instilled intranasally in mice. Histologic changes were examined in wild-type and IgE-deficient (IgE –/–) animals. The effect of eotaxin administration was assessed in wild-type and IL-5 transgenic mice. Results: Af-treated mice developed a nasal mucosal eosinophil influx comparable to that described for humans. This histology was distinct from that observed in a murine model of Af-induced asthma. The pathology appeared over a time course similar to that reported for human subjects. There was no difference in the intensity of the mucosal inflammatory infiltrate of Af-treated IgE –/– mice compared with wild-type mice. Eotaxin was able to recruit eosinophils to the mucosa but only in IL-5 transgenic animals. Conclusion: We describe a murine model for allergic rhinitis with an eosinophilic infiltrate comparable to that found in human disease and have demonstrated that rhinitis can arise in the absence of IgE. We have shown that the eosinophil influx can be induced by eotaxin in the presence of IL-5. (J Allergy Clin Immunol 1998;102:65-74.)

Local over-expression of IL-5 within murine small bowel induces local and mucosal eosinophilia without alterations in muscle function

Local over-expression of IL-5 within murine small bowel induces local and mucosal eosinophilia without alterations in muscle function

Generation of clusters of free eosinophil granules (Cfegs) in seasonal allergic rhinitis.

Generation of clusters of free eosinophil granules (Cfegs), through lysis of eosinophils, has recently been proposed as a major paradigm for ultimate activation of airway mucosal eosinophils. In the present study involving patients with seasonal allergic rhinitis, we have investigated whether generation of Cfegs in the nasal mucosa is a feature of allergic rhinitis. Nasal mucosal biopsies were obtained before and late in a birch-pollen season, and were subjected to histochemical staining of eosinophil peroxidase. In biopsies obtained before the pollen season, a few, intact eosinophils were observed, and Cfegs were scarce. In biopsies taken during the pollen season, the numbers of eosinophils were increased about 10-fold (P < 0.05) and the Cfegs about 25-fold (P < 0.05). We conclude that generation of Cfegs is a significant feature of seasonal allergic rhinitis and that this process represents the ultimate activation of mucosal eosinophils in this disease.

Induction of Pulmonary Allergic Responses by Antigen-Specific Th2 Cells

The development of pulmonary allergic responses was examined in mice following pulmonary transfer of Ag (conalbumin)-specific Th2 cells. The levels of serum-specific IgE, cellular infiltrates, airway mucus goblet cells, and airway responsiveness were analyzed and compared with those in Ag-sensitized and -challenged mice. Pulmonary transfer of the conalbumin-specific Th2 clone (D10) induced, in an Ag-specific manner, high levels of the Th2 cytokines IL-4 and IL-5 in the bronchoalveolar lavage fluids and mucosal eosinophils, concomitant with an increase in airway responsiveness. The D10 cell-induced responses were seen in the absence of serum specific IgE. In the presence of Ag, the transferred D10 cells not only remained in the lungs, but also increased in number 72 h post-cell transfer. Although significantly higher levels of IL-4 and IL-5 in the bronchoalveolar lavage fluids were found in D10-transferred mice, the levels of pulmonary eosinophilia, mucus goblet cells, and airway responsiveness were significantly lower than those in Ag-sensitized and -challenged mice. These results demonstrate that although Ag-specific activation of Th2 cells at mucosal sites is able to mediate the recruitment of eosinophils and the subsequent induction of airway hyper-responsiveness, the more severe pulmonary allergic responses were observed only in mice sensitized and challenged with Ag.

The expulsion of Echinostoma trivolvis: worm kinetics and intestinal reactions in C3H/HeN mice treated with dexamethasone.

C3H/HeN mice were each infected with 40 Echinostoma trivolvis metacercarial cysts on day 0, given intramuscular injections of dexamethasone (DEX) daily for 30 days, and necropsied on days 5, 8, 12, 15, 20 and 30 p. i. Control mice were each infected with 40 echinostome cysts on day 0, but were not treated with DEX and necropsied on the same days as the DEX-treated mice. DEX treatment caused an inhibition of worm expulsion and suppressed the increase in goblet cell numbers that peaked around day 12 p. i. in the untreated control mice. Increase in the number of mucosal mast cells and eosinophils in the control mice that peaked around day 15 and 12 p. i., respectively, was also suppressed by the DEX treatment. The mean body area of the worms from the DEX-treated mice was about the same as that of the control worms on day 5 p. i., and then significantly greater than the control worms on days 8 and 12 p. i. The worms in the treated mice continued to grow until the end of the experiment, on day 30 p. i. Enzyme-linked immunosorbent assay (ELISA) showed that serum IgM from the treated and control mice increased from day 12 p. i., peaked on day 15 p. i., and then decreased. An IgM titre of the treated mice was slightly higher than that of the controls. No marked rise in IgG and IgA titres occurred throughout the experiment in both groups.

The pathology of fibrosing colonopathy of cystic fibrosis: A study of 12 cases and review of the literature

The authors studied eight colectomy and eight biopsy specimens from 12 patients with cystic fibrosis who had developed fibrosing colonopathy, a complication observed in patients receiving high-strength enzyme replacement. The colectomies originated from five male and three female patients ranging in age from 18 months to 6 years. Five individuals had localized strictures of the right colon and three had stenosing fibrosis of the entire colon. The affected colon had a cobblestone appearance, submucosal fibrosis, thickening of the muscularis propria and chronic mucosal inflammation in all patients, with active cryptitis in four. Moderate to severe infiltration by eosinophils, with increase in the number of mast cells, and widespread interruption of the muscularis mucosa were present in every case. Four colectomies were preceded by endoscopic biopsies; four patients who have not undergone surgery also underwent biopsy. All the biopsies showed evidence of active or chronic inflammation, and all had increased mucosal eosinophils. Prolonged colonic mucosal contact with either the enzymes and/or the enteric coating itself may lead to mucosal colonic ulceration and inflammation. Topical allergy may then promote the stenosing fibroplasia.

Eosinophilic Infiltration of the Enteric Neural Plexuses in Hirschsprung'S Disease

Inflammatory infiltrations of the enteric plexuses are uncommon and are usually lymphoplasmacytic. Within the past 15 years, nine pediatric cases in which a predominantly eosinophilic infiltrate of the gastrointestinal wall with a predilection for the myenteric (Auerbach's) and deep submucosal (Henle's) plexuses were seen at our institution. Two were neonates without gastrointestinal abnormalities who expired shortly after birth. Seven were patients with short-segment Hirsch-sprung's disease. There was a mild increase in mucosal eosinophils in the overlying mucosa and only one patient had peripheral eosinophilia. Follow-up data obtained 1 month to 7 1/2 years after biopsy revealed no development of inflammatory bowel disease, connective tissue disease, malignancy, allergic disorder, or intestinal dysmotility. The proximal location of the infiltrate suggests that it may represent a secondary finding rather than a primary cause of aganglionosis.

Increased expression of mRNA encoding RANTES and MCP-3 in the bronchial mucosa in atopic asthma.

The selective recruitment of eosinophils into the mucosal lining of the airways is a prominent feature of atopic asthma, and is believed to be an important component in the disease pathogenesis. The precise stimuli responsible for the influx of eosinophils remain unclear. Using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique, the numbers of copies (relative to the "housekeeping" gene beta-actin) of messenger ribonucleic acid (mRNA) encoding the eosinophil-active chemotactic cytokines, the factor regulated upon activation in normal T-cells expressed and secreted (RANTES) and monocyte chemotactic protein-3 (MCP-3), was measured in bronchial biopsies from atopic asthmatic patients (n = 9), and compared with atopic nonasthmatic (n = 8) and nonatopic nonasthmatic (n = 8) control subjects. In addition, further biopsies from each subject were prepared for immunohistochemistry and the numbers of activated (EG2+) eosinophils measured. The expression of RANTES mRNA was significantly elevated in the atopic asthmatic group as compared to the atopic nonasthmatic controls (p = 0.013) and the nonatopic nonasthmatic controls (p = 0.007). Similarly, the expression of mRNA encoding MCP-3 was significantly elevated in the atopic asthmatic group, relative to the atopic nonasthmatic controls (p = 0.014) and the nonatopic nonasthmatic control group (p = 0.011). Elevated RANTES and MCP-3 mRNA expression was associated with significantly increased numbers of bronchial mucosal eosinophils in the atopic asthmatic patients as compared to the atopic nonasthmatic (p = 0.03) and nonatopic nonasthmatic (p = 0.006) control subjects. In conclusion, we have identified elevated expression of messenger ribonucleic acid encoding RANTES and monocyte chemotactic protein-3 in the bronchial mucosa of atopic asthmatic patients relative to controls. These findings are compatible with the hypothesis that eosinophil-active beta-chemokines play a role in the mechanism of eosinophil recruitment to the asthmatic bronchial mucosa.

Sequential cellular and humoral responses in the abomasal mucosa and blood of Romney sheep dosed with Trichostrongylus axei

Sequential cellular and humoral responses in the abomasal mucosa and blood of Romney sheep dosed with Trichostrongylus axei. International Journal for Parasitelogy 26: 765–773. Abomasal cannalae were surgically placed in 7 2-year-old New Zealand Romney sheep which had been maintained parasite-free from birth. Four of these sheep were randomly selected and dosed orally with 10,000 infective Trichostrongylus axei larvae per week for 8 weeks, while the remsining 3 sheep served as unfufected controls. Abomasal biopsy, blood and faecal samples were obtained from all sheep at regular intervain from 5 days before and until 58 days after the first infection. The sheep were then killed, worm burdens assessed and abomasal and small intestinal samples collected. Faccal egg counts of all 4 dosed sheep were low and only one (No. 701) had a substantial worm burden (8400) post mortem. Overall, levels of mucosal mast cells/globule leukocytes, eosinophils, T19 + cells and larval migration inhibitory activity incressed signlfleastly in the abomasal mucosa of the dosed sheep compared to the controls. The CD4 +:CD8 + cell ratio in the abornasal mucosa of the dosed sheep also increased compared to that of the controls ( P=0.06). In blod, T. axei-specific antibody (total and IgG 1) and eosinophil numbers increased signiflenatly in the dosed sheep. Mucosal cells staining for IgE (IgE +), and blood and mucosal eosinophils showed the earliest substantive increases in number followed by increases in specific serum antibody levels, numbers of mucosal cells fluorescing under UV light (UVf) and T19 + cells. The difference in the IgE + and UVf cell response indicated that expession of globule leukocyte numbers lagged behind that of mucosal mast cells. The results supported the concept of CD4 + T cell help in the abomasal mucosa and defined the sequential expression of compoments of the immunological responses potentially mediating resistance to T. axei. In sheep No. 701, persistence of adult worms was associated with lower mucosal IgE + cell and eosinophil responses compared with the other dosed sheep.

Fluticasone propionate aqueous nasal spray compared with terfenadine tablets in the treatment of seasonal allergic rhinitis

Comparative studies with topical corticosteroids and antihistamines for treatment of allergic rhinitis have not always demonstrated clear distinctions between the two on the basis of therapeutic efficacy. This study was designed to compare the efficacy and tolerability of fluticasone propionate aqueous nasal spray with those of terfenadine in the treatment of seasonal allergic rhinitis. Three hundred forty-eight patients with allergic rhinitis were given fluticasone propionate aqueous nasal spray (200 micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 4 weeks in a multicenter, randomized, double-blind, double-dummy, parallel-group study. Clinician-rated total nasal symptom scores after 1, 2, 3, and 4 weeks of therapy and patient-rated total nasal symptom scores throughout treatment were significantly (p <0.05) lower in the fluticasone propionate group compared with the terfenadine group or the placebo group. Terfenadine was not statistically different from placebo on the basis of clinician-related nasal symptom scores, except for sneezing. Total nasal airflow, measured by rhinomanometry, significantly (p <0.05) improved in the fluticasone propionate group compared with the terfenadine group or the placebo group. More fluticasone propionate-treated patients compared with placebo-treated patients had reduced nasal mucosal eosinophil counts after 4 weeks of therapy (p <0.05). No serious or unusual drug-related adverse events were reported. Morning plasma cortisol concentrations after 4 weeks of therapy did not differ among groups. Fluticasone propionate aqueous nasal spray is more effective than terfenadine tablets for treatment of seasonal allergic rhinitis.

Clinical implications of the pharmacological profile of Tilarin.

The pharmacological activity of nedocromil sodium is extensive and the compound should affect a variety of inflammatory processes by preventing activation of the involved cells or blocking release of their mediators. Some in vitro actions of nedocromil sodium are particularly relevant to the mechanisms of allergic rhinitis, and the response of the nasal epithelium to pollutants such as ozone. The effects of nedocromil sodium on mucosal mast cells, eosinophils, sensory nerves and nasal epithelial cells can each be linked to its potential clinical effectiveness by our own biopsy studies from patients with active allergic rhinitis. Nedocromil sodium has been shown to modulate production of a number of powerful cytokines, such as GM-CSF and TNF alpha, which are produced by the human nasal epithelium, as well as by involved inflammatory cells and lymphocytes, and which orchestrate the inflammatory response to allergen or to pollutant provocation. So, in addition to inhibiting activated mast cells and eosinophils, nedocromil sodium acts on the nasal epithelium itself to prevent further accumulation of these cells and thus to break the inflammatory chain of events. On this evidence of its preclinical activity, nedocromil sodium promises to become a very useful topical treatment for allergic rhinitis.

Long-term outcome of idiopathic hypereosinophilic syndrome — transition to eosinophilic gastroenteritis and clonal expansion of T-cells

We describe a patient with idiopathic hypereosinophilic syndrome, without initial gastrointestinal symptoms, and their transition to eosinophilic gastroenteritis. This patient, a 65-year-old man, presented with fever, constitutional symptoms, peripheral and bone marrow eosinophilia 20 years ago. During the course of the disease, diarrhoea and malabsorption became prominent, whereas bone marrow eosinophilia regressed completely and blood eosinophilia regressed partially. Biopsies showed a severe eosinophilic gastroenteritis of the mucosal type involving the stomach, small bowel and colon. During the final years of the patient's disease, mucosal eosinophilia became less intense and a mucosal infiltration with T-cells dominated. At autopsy, immunopathological studies of small intestines and colon specimens showed a clonal expansion of morphologically normal T-cells in the intestinal mucosa, which expressed the abnormal phenotype CD2+CD3+CD4-CD5-CD8-. Flow cytometry examination of peripheral blood revealed a corresponding abnormal population of CD3+CD4-CD8- T-cells, indicating a systemic spread of the process. The patient eventually died of non-obstructive small bowel infarction with peritonitis 20 years after the onset of the first symptoms. We postulate that the destructive eosinophilic/lymphocytic inflammation is caused by a clonal proliferation of T-lymphocytes with probable secretion of Type 2 T(helper) cell cytokines and consecutive stimulation of eosinophils.

Dietary protein influences upon immunity to Nematodirus battus infection in lambs

Several indices of the immune response to Nematodirus battus infection in lambs offered differing levels of dietary protein were quantified. Lambs were offered either a complete basal ruminant diet (13.2% crude protein (CP)) or the same diet supplemented with fish meal as a source of rumen bypass protein (18.3% CP). Lambs from each dietary treatment group were given either a 7-week continuous trickle infection with N. battus L 3 or remained uninfected. All lambs were drenched with anthelmintic at week 8 post-infection (PI), challenged with a single dose of 30 000 N. battus L 3 1 week later, and killed 9 days post-challenge (PC). Previous infection induced a significant reduction in worm burdens ( p < 0.001) and enhancement of immune responses when compared to challenge controls. Among previously infected lambs, protein supplementation did not reduce worm burdens significantly, although there was a trend for fewer worms in the supplemented lambs. However, a significant increase in mucosal globule leucocyte ( p < 0.05) and eosinophil ( p < 0.05) numbers was evident. Supplementation ( p < 0.05) and previous infection ( p < 0.001) both enhanced serum anti-worm IgG titres over time. Peripheral blood eosinophil counts were not affected by supplementation but were significantly elevated over time as a result of previous infection ( p < 0.001). Since there were no significant differences in worm burdens of supplemented and unsupplemented previously infected lambs, it was of interest to determine whether lambs possessed an innate ability to regulate their parasite burden. Hence they were re-grouped based on an arbitrary cut-off burden of 1000 worms. Hihh responders (HR) had burdens below 1000 worms, while low responders (LR) had burdens above this value and challenge controls were pooled. The data were re-analyzed based on these groupings and showed significant reduction in worm burdens between all three groups ( p < 0.001). Globule leucocytes were the only cell type that appeared to be significantly more abundant in the intestinal mucosa of HR ( p < 0.001). Serum antibody responses ( p < 0.05) and peripheral blood eosinophil counts ( p < 0.01) were significantly elevated over time in accord with the degree of responsiveness. The results of this study suggest that supplementation of protein upon an adequate basal diet of lambs previously exposed to N. battus does not significantly enhance worm regulation despite significant increases in cellular and antibody responses. The immunity acquired is characterized by reduction in worm burdens, elevated anti-worm antibodies and a cellular inflammatory response. The identification of HR and LR essentially shows that when the protein supply is adequate, the predominant host effect influencing the pathogenicity of the parasites is the level of genetically determined susceptibility of the host.