bluuebunny/crossref_metadata_2025 huggingface dataset:
Thymus size and head circumference at birth and the development of allergic diseases
Authors: Benn C. S. , Jeppesen D. L. , Hasselbalch H. , Olesen A. B. , Nielsen J. , Björkstén B. , Lisse I. , Aaby P.
Published: March 2003

Background The positive association between a large head circumference at birth and total serum IgE levels has been suggested to be due to negative associations between head circumference at birth and thymus development and between thymus development and total serum IgE levels.

Objectives To examine the associations between head circumference and thymus size at birth and the development of allergic disease.

Methods The size of the thymus was assessed by sonography during the first week of life in 149 healthy term infants. Information on birth characteristics and mode of delivery was collected at delivery. The presence of allergic disease was assessed 5 years later by mailed questionnaires, which were returned by 85% of the eligible families.

Results At birth, head circumference was positively associated with thymus size (P < 0.001). In all, 27 (23%) of the children had developed at least one allergic disease. Multivariate analysis revealed that both parental allergy (Prevalence Ratio and 95% CI) = 3.18 (1.49–6.78)) and caesarean delivery (2.62 (1.48–4.64)) were independently correlated with allergic disease, whereas thymus size was not.

Conclusions Our study does not support that a large head circumference is associated with a small thymus size, nor that a small thymus size is associated with allergic disease. Whether thymus size at birth is related to total serum IgE levels still remains to be elucidated.
Expression of C–C chemokine TARC in human nasal mucosa and its regulation by cytokines
Authors: Terada N. , Nomura T. , Kim W. J. , Otsuka Y. , Takahashi R. , Kishi H. , Yamashita T. , Sugawara N. , Fukuda S. , Ikeda‐Ito T. , Konno A.
Published: March 2003

Background Although interleukin (IL)‐4 and IL‐5 have been demonstrated to play a critical role in the pathophysiology of allergic diseases such as allergic rhinitis, the mechanism that causes the predominance of Th2 lymphocytes has yet to be clarified. Thymus and activation‐regulated chemokine (TARC) has been known to facilitate the recruitment, activation and development of Th2 polarized cells, leading investigators to suggest a role for TARC in the development of Th2 responses.

Objective To gain a better understanding of the role of TARC in the pathogenesis of allergic rhinitis we investigated the cellular sources of this chemokine in nasal mucosa. In addition, the effect of cytokines on TARC production has been investigated.

Methods The expression of TARC in human nasal mucosa was assessed by immunohistochemistry. To study the effect of cytokines on TARC production, epithelial cells, endothelial cells and fibroblasts, isolated from inferior nasal mucosa samples, were stimulated by a variety of cytokines including IL‐4, IL‐13, tumour necrosis factor (TNF)‐α and interferon (IFN)‐γ.

Results Epithelial cells in nasal mucosa in subjects with allergic rhinitis expressed higher signal level than those in non‐allergy patients. Combined stimulation with IL‐4 and TNF‐α, as well as IL‐13 and TNF‐α, synergistically induced TARC expression in epithelial cells. Furthermore, the amount of TARC induced by these cytokines was higher in epithelial cells obtained from patients with allergic rhinitis than in those from non‐allergic patients.

Conclusion These results demonstrate a crucial role of nasal epithelial cells in the expression of TARC, and that Th2 cytokine IL‐4 and IL‐13 may promote Th2 responses by inducing TARC production from epithelial cells.
Differential inhibition of inflammatory effector functions by petasin, isopetasin and neopetasin in human eosinophils
Authors: Thomet O. A. R. , Wiesmann U. N. , Blaser K. , Simon H.‐U.
Published: March 2003

Background Priming of eosinophils with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and subsequent stimulation with platelet‐activating factor (PAF) or the anaphylatoxin C5a is associated with a rapid production of leukotrienes (LTs) and release of eosinophil cationic protein (ECP).

Objective This study was designed to determine the effects of the sesquiterpene esters petasin, isopetasin and neopetasin on LT generation and ECP release in eosinophils in vitro.

Methods The model of eosinophil activation described above was used to induce LT production and ECP release. Cells were incubated with petasins and control inhibitors prior to priming and stimulation. To analyse intracellular steps of eosinophil activation and determine potential drug targets, some key signalling events were studied. Activity of cytosolic phospholipase A2 (cPLA2) was measured by analysing the generation of arachidonic acid (AA). Translocation of 5‐lipoxygenase (5‐LO) was observed using immunofluorescence microscopy. Intracellular calcium concentrations [Ca2+]i were measured by a bulk spectrofluorometric assay.

Results Whereas all three compounds inhibited LT synthesis, ECP release from eosinophils was blocked by petasin only, but not isopetasin or neopetasin. Similarly, PAF‐ or C5a‐induced increases in [Ca2+]i were completely abrogated by petasin only, whereas isopetasin and neopetasin had significant lower blocking efficacy. Moreover, only petasin, but not isopetasin or neopetasin, prevented increases in cPLA2 activity and 5‐LO translocation from the cytosolic compartment to the nucleus envelope in calcium ionophore‐stimulated eosinophils.

Conclusion These data suggest that different petasins may at least partially block different intracellular signalling molecules. To reduce LT synthesis, isopetasin and neopetasin may act at the level of or distal to 5‐LO. In contrast, petasin may inhibit inflammatory effector functions in human eosinophils by disrupting signalling events at the level of or proximal to phospholipase Cβ (PLCβ), besides its potential inhibitory activity within mitogen‐activated protein kinase (MAPK) and LT pathways.
An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma
Authors: Ragab S. , Parikh A. , Darby Y. C. , Scadding G. K.
Published: March 2003

Background Nasal polyposis occurs frequently in patients with intrinsic asthma, especially in those who are aspirin sensitive. It can be difficult to treat effectively, even with surgery and regular topical intranasal corticosteroids many patients are still symptomatic.

Objective To investigate the response to montelukast, a leukotriene D4 receptor antagonist, as an add‐on therapy to topical and inhaled corticosteroids in patients, both aspirin sensitive (AS) and aspirin tolerant (AT), with nasal polyposis and asthma.

Methods Nasal polyposis symptoms were assessed by visual analogue scales; nasal polyps were assessed by nasendoscopy and via the measurement of nasal volumes by acoustic rhinometry. The nasal airway was assessed by nasal inspiratory peakflow (NIPF). Asthma was monitored using symptom scores and peak expiratory flow measurements. Aspirin sensitivity was assessed by history together with intranasal lysine aspirin challenge. Upper and lower airway nitric oxide measurements were made before and during treatment.

Results Clinical subjective improvement in nasal polyposis occurred in 64% AT (P < 0.01), patients and 50% AS patients (P > 0.05); asthma improvement in 87% AT and 61% AS patients (P < 0.05 for both). Objective changes in peak flow occurred only in AT patients (P < 0.05). Acoustic rhinometry, nasal inspiratory peak flow and nitric oxide levels did not change significantly in any group, however, correlations were seen between nitric oxide levels and polyp scores and between nitric oxide levels and acoustic rhinometry changes. Improvement on montelukast therapy was not associated with any of the following variables: age, sex, skin prick test positivity, disease duration or aspirin sensitivity. (P > 0.05 for all).

Conclusion The findings are consistent with a subgroup of nasal polyps/asthma patients in whom leukotriene receptor antagonists are effective. This is not related to aspirin sensitivity. Further placebo‐controlled studies need to be undertaken.
Peripheral blood CD4+ and CD8+ T cell type 1 and type 2 cytokine production in atopic asthmatic and normal subjects
Authors: Cho S.‐H. , Stanciu L. A. , Begishivili T. , Bates P. J. , Holgate S. T. , Johnston S. L.
Published: March 2003

Background Increased production of IL‐4 and IL‐5 and decreased production of IFN‐γ by CD4+ T cells has been implicated in asthma pathogenesis. However, CD8+ T cells also produce type 1 and type 2 cytokines and the relative roles of CD4+ and CD8+ T cell cytokine production in asthma have not been previously studied.

Objective To determine the production of the type 1 and type 2 cytokines by CD4+ and CD8+ T cell subsets in asthmatic and normal subjects.

Methods Intracellular cytokine staining for IL‐4, ‐5, ‐10, ‐13 and IFN‐γ was analysed in peripheral blood CD4+ and CD8+ T cells from 24 atopic asthmatic and 20 normal subjects.

Results Both subsets of T cells produced all cytokines studied and there were no significant differences between CD4+ and CD8+ T cells in their capacity to produce either type 1 or type 2 cytokines. There were significantly increased frequencies of IFN‐γ‐positive CD4+ (13.1 ± 2.4%, vs. 7.3 ± 1.4%) and CD8+ (20.0 ± 2.9%, vs. 9.6 ± 2.1%) T cells in asthmatic subjects compared with normal subjects (P < 0.05), but not in frequencies of CD4+ or CD8+ T cells staining positively for IL‐4, ‐5, ‐10 or ‐13.

Conclusion The frequencies of peripheral blood CD8+ T cells producing type 1 and type 2 cytokines are comparable with the frequencies of CD4+ T cells. There was an increased frequency of IFN‐γ producing CD4+ and CD8+ T cells in asthmatic compared with normal subjects. Further studies investigating T cells derived from the airways and investigating various stages within the disease process are required to further elucidate the importance of type 2 and type 1 T cell cytokine production in the pathogenesis of human allergic disease.
Carbohydrates expressed on Aspergillus fumigatus induce in vivo allergic Th2‐type response
Authors: Yamashita Y. , Okano M. , Yoshino T. , Hattori H. , Yamamoto T. , Watanabe T. , Takishita T. , Akagi T. , Nishizaki K.
Published: March 2003

Background  The mould Aspergillus fumigatus (Af) causes several forms of Th2‐biased diseases such as Type I respiratory allergies. This mould contains abundant carbohydrates including glucan, chitin and galactomannan. However, little is known on whether these carbohydrates directly drive Th2 responses in vivo.

Objective  We sought to determine the relative role of carbohydrates expressed on crude extracts of Af in the induction of Th2‐type antibody production and local eosinophila in mice.

Methods  Carbohydrates on native Af were destroyed by sodium metaperiodate under mild conditions. CBA/J mice were sensitized intranasally with native, periodate‐treated or mock‐treated Af. Histologic changes and production of Af‐specific IgE, IgG1 and IgG2a, as well as serum total IgE were determined. Inhibition ELISA for Af‐specific IgE was performed using periodate‐treated Af as an inhibitor.

Results  Mice sensitized with periodate‐treated Af displayed significant decreases in both total and specific IgE levels in comparison to mice sensitized with native or mock‐treated Af. Furthermore, sensitization and subsequent challenge with periodate‐treated Af significantly reduced the degree of eosinophil recruitment into the nasal mucosa, compared to the controls. On the other hand, competitive inhibition showed that periodate‐treated Af could inhibit binding between native Af and specific IgE in a similar manner to that of native and mock‐treated Af.

Conclusion  These results suggest that carbohydrates on Af play a key role as internal adjuvants in inducing the allergic Th2‐type response and are not the targets of the induced IgE response.
Lack of association between a polymorphism in the interleukin‐13 gene and total serum immunoglobulin E level among nuclear families in Costa Rica
Authors: Celedón J. C. , Soto‐Quiros M. E. , Palmer L. J. , Senter J. , Mosley J. , Silverman E. K. , Weiss S. T.
Published: March 2003

Background IL‐13 has been implicated in the pathogenesis of asthma and in the regulation of IgE synthesis in humans. Single nucleotide polymorphisms (SNPs) in the IL‐13 gene have been associated with asthma and total serum IgE level in Caucasian populations.

Objective To test for genetic association between an SNP in exon 4 of the IL‐13 gene (IL‐13 + 2044 or Arg130Gln) and total serum IgE level and asthma‐related phenotypes in a population with high prevalence of asthma living in Costa Rica.

Methods Family‐based association study.

Results Among 83 Costa Rican school children with asthma and their parents (249 individuals), there was no evidence of linkage disequilibrium between the IL‐13 + 2044 SNP and any of the outcomes of interest (total serum IgE level on a logarithmic scale, number of positive skin tests to aeroallergens, and asthma). These results were not significantly changed after adjustment for age and gender.

Conclusions No significant evidence of linkage disequilibrium between an SNP in exon 4 of the IL‐13 gene and total serum IgE level, sensitization to allergens or asthma was found in a family‐based association study in Costa Rica.
Mite avoidance can reduce air trapping and airway inflammation in allergic asthmatic children
Authors: Peroni D. G. , Piacentini G. L. , Costella S. , Pietrobelli A. , Bodini A. , Loiacono A. , Aralla R. , Boner A. L.
Published: March 2003

Background We investigated the effects of prolonged allergen avoidance in 18 house dust mite‐sensitized asthmatic children during a prolonged residential period at a high altitude, allergen‐free environment.

Methods Evaluations of residual volume (RV) and exhaled nitric oxide (eNO) were performed (i) at admission to the residential house in September, (ii) in December after 3 months of stay, (iii) in January after 15 days at home, exposed to allergens, and (iv) in June after 9 months of stay.

Results During the study period RV showed a significant decrease in December (from 117.5 ± 7.7% to 96.5 ± 3.2%) (P < 0.02) and a following increase in January (126.2 ± 17.2%), after allergen re‐exposure (P < 0.03). RV decreased again in June at the end of the study period (91.1 ± 6.0%) (P = 0.001). FEV1, FEF25−75 and VC values did not present significant variations. ENO showed a significant decrease in December after 3 months at high altitude (from 21.3 ± 3.9 p.p.b. to 11.9 ± 1.7 p.p.b.) (P = 0.03), but no further significant change. No correlation was found between lung volumes and eNO, probably reflecting different aspects of asthma.

Conclusions Results suggest that RV may be more sensitive than other respiratory function parameters in identifying children with air trapping, being influenced significantly as the inflammatory indices by effective allergen avoidance/exposure regimen.
Rapid response of circulating myeloid dendritic cells to inhaled allergen in asthmatic subjects
Authors: Upham J. W. , Denburg J. A. , O'Byrne P. M.
Published: March 2003

Background Dendritic cells (DC) are thought to play a key role in the initiation and maintenance of T cell immunity to inhaled antigens. While the density of DC within the bronchial mucosa is increased in stable asthma, there is little information currently available concerning the effects of allergen inhalation on DC in subjects with asthma.

Objectives To enumerate changes in the numbers of circulating CD33+ myeloid DC in asthmatics, before and after allergen challenge.

Methods Blood DC numbers were enumerated by flow cytometry before and at 3, 6 and 24 h after inhaled allergen and diluent in 10 mild, allergic asthmatic subjects.

Results Blood DC numbers rapidly fell from 3.42 ± 0.30 × 107/L at baseline, to 2.10 ± 0.17 × 107/L by 3 h post‐challenge (P < 0.01), and remained significantly below baseline values at both 6 and 24 h following allergen challenge. No such changes in DC numbers were noted after diluent challenge. A similar, early fall in circulating lymphocytes was also noted post‐allergen challenge, whereas changes in circulating eosinophil and neutrophil numbers occurred more slowly.

Conclusions A significant proportion of myeloid DC rapidly ‘disappear’ from the circulation following allergen inhalation, suggesting that margination of circulating myeloid DC, and their recruitment into the airway mucosa, is an important feature of the immune response to inhaled allergen.
Improvement in psoriasis after intradermal administration of delipidated, deglycolipidated Mycobacterium vaccae (PVAC™): results of an open-label trial
Authors: Balagon M. V. , Tan P. L. , Prestidge R. , Cellona R. V. , Abalos R. M. , Tan E. V. , Walsh G. P. , Watson J. D. , Walsh D. S.
Published: March 2003

The aim of new treatments for psoriasis is to induce extended remissions with fewer side-effects. Previous studies suggest that Mycobacterium vaccae, a harmless organism prepared as a heat-killed suspension, may induce periods of remission in some psoriasis patients after intradermal administration. To assess a more potent derivative of M. vaccae, we conducted an open-label study in which 20 patients with moderate to severe psoriasis (Psoriasis Area and Severity Index of 12–35) received two intradermal inoculations of heat-killed, delipidated, deglycolipidated M. vaccae (DD-MVAC or ‘PVAC’) in lesion-free deltoid skin, separated by a period of 3 weeks. Twelve weeks after the injections, 13 out of 20 patients (65%) showed marked improvement in the PASI score (> 50% reduction), three were unchanged (< 25% reduction), three had worsened (> 5% increase), and one was withdrawn from the trial because of an exfoliative flare. At 24 weeks, 13 out of 19 patients continued to show > 50% improvement that, in some, lasted for 6 months or longer. Patients classified as good responders at 12 or 24 weeks were then offered additional PVAC injections after 24 weeks if the PASI reached 8 or higher. Intra-dermal administration of PVAC was safe, well tolerated, and induced clinically significant improvement in many psoriasis patients. A randomized, double-blind, controlled study is warranted.
Severe cutaneous reaction to CS gas
Authors: Varma S. , Holt P. J. A.
Published: March 2003

Tear gas is used throughout the World for control of riots and civil disobedience. CS gas as used by the UK police force is issued as a ‘spray’ and is 5% CS in methylisobutylketone (MIBK), a potent irritant. Assaults on police officers in forces issued with CS spray have fallen significantly over the past 3 years, whilst having risen in areas without it. Thus, CS gas appears to be an effective deterrent. However, significant cutaneous reactions can occur as a result of exposure. We report a severe contact dermatitis to CS gas to highlight the clinical features. The nature of CS gas and potential cutaneous adverse reactions are discussed.
Subclass distribution of IgA antibodies in saliva and serum after immunization withHaemophilus influenzaetype b conjugate vaccines
Authors: Kauppi-Korkeila M , Saarinen L , Eskola J , KÄyhty H
Published: March 2003

IgA subclass distribution of antibodies against capsular polysaccharide (PS) of Haemophilus influenzae type b (Hib) was studied in saliva and serum samples of children vaccinated with two (n = 58) or three doses (n = 53) of Hib vaccine. One month after the second dose of Hib conjugate vaccine, at 7 months old, 40% of the children had IgA1 and 41% had IgA2 anti-Hib PS antibodies in saliva. One month after the third dose, at 15–25 months old, IgA1 was the predominating subclass; 72% of the children had IgA1, 26% had IgA2 anti-Hib PS in saliva. The mean concentration of IgA1 anti-Hib PS, expressed as optical density (OD) values, was significantly higher after three doses (OD 80.7) than after two doses (OD 18.9). The mean concentration of IgA2 did not change significantly after the third dose (OD 23.8 after two doses, OD 18.1 after three doses). In serum, IgA1 anti-Hib PS predominated both after two (17% had IgA1, none had IgA2) and three doses (72% had IgA1, 4% had IgA2) of Hib vaccine. In conclusion, both IgA1 and IgA2 anti-Hib PS were found in saliva of immunized children after two doses of Hib conjugate vaccine, whereas the third vaccine dose induced a shift towards IgA1 anti-Hib PS dominance in saliva.
Suppression of IL-6 biological activities by activin A and implications for inflammatory arthropathies
Authors: YU E W , Dolter K E , Shao L-E , YU J
Published: March 2003

Activin A is a cytokine whose multiple functions have yet to be fully determined. In this study, the role of proinflammatory cytokines in regulatory control of activin A production was shown in synoviocytes and chondrocytes. Additional facets of functional inflammation-related activities of activin A were also determined. Results showed that activin A concentrations in the synovial fluid of patients with rheumatoid arthritis and gout were elevated relative to those in patients with osteoarthritis. Further studies showed that production of activin A by synoviocytes and chondrocytes in culture was stimulated by cytokines such as IL-1, transforming growth factor-beta (TGF-β), interferon-gamma (IFN-γ), and IL-8, consistent with previous studies in regard to the control of activin A production in marrow stromal cells and monocytes by cytokines, glucocorticoids and retinoic acid. In addition, the relationship of activin A to IL-6-induced biological activities was investigated. Three major IL-6 activities involved in inflammatory responses were found to be suppressed by activin A. In a dose-dependent manner, activin A efficiently suppressed IL-6-induced proliferation of 7TD1 B lymphoid cells, phagocytic activity of monocytic M1 cells, and fibrinogen production in HepG2. Therefore, it is likely that activin A serves as a suppressor for IL-6, dampening inflammatory responses, and has the potential to perform some previously unrecognized roles in inflammation.
A 75-kD autoantigen recognized by sera from patients with X-linked autoimmune enteropathy associated with nephropathy
Authors: Kobayashi I , Imamura K , Yamada M , Okano M , Yara A , Ikema S , Ishikawa N , Kobayashi K , Sakiyama Y
Published: March 2003

Autoimmune enteropathy (AIE) is a rare disorder characterized by intractable diarrhoea and anti-enterocyte autoantibody. In this study, we detected a 75-kD autoantigen which distributed through the whole intestine and the kidney, as assessed by Western blot analysis using sera from two unrelated cases of AIE associated with nephropathy. Our results suggest that the detection of the autoantibody against the 75-kD antigen has a diagnostic value in AIE and that the autoimmune reaction against the 75-kD antigen may be implicated in the development of intestinal and renal tissue damage in this rare disorder.
Cellular immunity in recurrent vulvovaginal candidiasis
Authors: Corrigan E M , Clancy R L , Dunkley M L , Eyers F M , Beagley K W
Published: March 2003

Impaired T cell function has been reported to predispose women to recurrent vulvovaginal candidiasis, but conflicting results have been noted in the literature. Most clinical episodes occur in the late luteal phase, suggesting hormonal influence on host resistance. The present study assesses the cellular immune responses of 28 women with recurrent vaginal candidiasis (patients) and 25 control women (controls), noting results in relation to whether the women were in the follicular or luteal phase of the menstrual cycle at the time of sampling. Candida-stimulated peripheral blood lymphocyte proliferation was significantly reduced in patients compared with controls. Interferon-gamma (IFN-γ) production in response to both Candida and purified protein derivative (PPD) stimulation was significantly lower in patients compared with controls. Skin test responses were comparable in both groups. A significant reduction in Candida-stimulated IFN-γ production was seen in patients but not controls in the follicular phase compared with those in the luteal phase. There was also a trend towards lower proliferation in response to Candida in patients but not controls in the follicular phase compared with patients in the luteal phase. These results suggest that there is a partial T cell dysregulation in recurrent vaginal candidiasis which may be exacerbated by the hormonal balance present during the follicular phase, correlating with the risk of clinical infection.
Heterogeneity in the occurrence of a subset of autoantibodies to glutamic acid decarboxylase in autoimmune polyendocrine patients with islet cell antibodies
Authors: Davenport C , Radford P M , AL-Bukhari T A M A , Lai M , Bottazzo G F , Todd I
Published: March 2003

Glutamic acid decarboxylase-65 (GAD-65) is a major target for autoantibodies and autoreactive T cells in patients with insulin-dependent diabetes mellitus (IDDM). Autoantibodies to GAD are also found in patients with stiff man syndrome (SMS) or polyendocrine autoimmunity (PE). The epitope specificities of autoantibodies to GAD in IDDM and SMS have been well documented, but the locations of autoantibody epitopes of GAD in PE patients have not been mapped. Thus, the properties of anti-GAD antibodies in PE patients (with or without diabetes) were investigated. The ability of PE serum antibodies to inhibit the binding of the mouse monoclonal antibody, GAD-6, to native GAD in ELISA was determined. For PE patients without diabetes, levels of inhibition of GAD-6 binding ranged from 0% to almost 70% and were unrelated to the level of binding of serum antibodies to GAD (P = 0.351) or to the functional affinities of these antibodies. This suggests differences in the epitope specificities of anti-GAD antibodies in different patients. Levels of inhibition were also unrelated to clinical condition. SMS antibodies showed similar levels of inhibition of GAD-6 binding. Similar analysis was applied to PE patients with diabetes and levels of inhibition of GAD-6 binding to GAD were determined. These ranged from 0% to 80%, and levels of inhibition were similar in samples taken before or after diabetes onset. There was no significant difference between anti-GAD antibodies from PE patients with or without diabetes in the range of abilities to inhibit GAD-6 binding to GAD, although the highest levels of inhibition were given by sera from non-diabetic patients. This raises the possibility of differential expression of subsets of anti-GAD antibodies in progressive versus slow or non-progressive anti-islet autoimmune responses. Serum antibodies of PE and SMS patients did not inhibit the binding of antibodies specific for the extreme C-terminus of GAD, indicating that this is not the site of the epitopes for the patients' antibodies or for GAD-6.
Effective prophylaxis of influenza A virus pneumonia in mice by topical passive immunotherapy with polyvalent human immunoglobulins or F(ab′)2 fragments
Authors: Ramisse M , Deramoudt F-X , Szatanik M , Bianchi A , Binder P , Hannoun C , Alonso J-M
Published: March 2003

The effectiveness of polyvalent plasma-derived human immunoglobulins (IVIG) in passive immunotherapy of influenza virus pneumonia was assessed, using the Strain Scotland (A/Scotland/74 (H3N2)) adapted to BALB/c mice by repeated lung passages. Haemagglutinin antibodies in two batches of IVIG at 10 mg/ml had a titre of 1/16. Intravenous injection of 1000–5000 μg of IVIG, 3 h after infection, gave 60–70% protection, whereas intranasal injection of 25–50 μg protected 90% of mice infected with a lethal dose of influenza virus. F (ab′)2 fragments were at least as protective as intact IVIG, suggesting that complement or Fcγ receptor-bearing cells were not required. Topical passive immunotherapy with IVIG or F(ab′)2 gave protection up to 8 h after infection, but not at 24 h, suggesting that anti-influenza A antibodies in IVIG, delivered locally, are only effective at early stages of the infectious process. The potential value of topical administration of IVIG or F(ab′)2 fragments for influenza A pneumonia prophylaxis was further demonstrated by the protective effects of their intranasal administration 24 h before challenge.
Differential expression of cytokine transcripts in human epithelial ovarian carcinoma by solid tumour specimens, peritoneal exudate cells containing tumour, tumour-infiltrating lymphocyte (TIL)-derived T cell lines and established tumour cell lines
Authors: Nash M A , Lenzi R , Edwards C L , Kavanagh J J , Kudelka A P , Verschraegen C F , Platsoucas C D , Freedman R S
Published: March 2003

T cell lines derived in low concentrations of recombinant IL-2 (rIL-2) from TIL of patients with epithelial ovarian carcinoma (EOC) often exhibit specific cytotoxicity against autologous tumour cells. However, the ability of T cells at the tumour site to respond to ovarian carcinoma cells may be affected by the production of cytokines by the various cell types present. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we investigated cytokine transcripts in: (i) established EOC tumour cell lines; (ii) solid tumour specimens or peritoneal exudate cells (PEC) from ascites or peritoneal washings of patients with EOC; and (iii) CD4+ TCRαβ+ and CD8+ TCRαβ+ TIL-derived T cell lines developed in rIL-2. We have found that (i) established EOC tumour cell lines expressed transcripts for transforming growth factor-beta 2 (TGF-β2) (7/7), but not IL-10 (0/7) or interferon-gamma (IFN-γ) (0/7) and rarely IL-2 (1/7); (ii) PEC expressed transcripts for IL-2 (12/13), IL-10 (9/13), and TGF-β2 (12/13), and less often, IFN-γ (3/13), whereas solid tumour specimens from eight patients with EOC expressed transcripts for IL-2 (4/8), TGF-β2 (4/8), and IL-10 (5/8), but not for IFN-γ (0/8); (iii) CD4+ TCRαβ+ T cell lines expressed transcripts for IFN-γ (4/4), IL-2 (4/4) and IL-10 (3/4), whereas CD8+ TCRαβ+ T cell lines expressed transcripts for IFN-γ (5/5), IL-2 (1/5) and IL-10 (2/5). None of these T cell lines expressed TGF-β2 transcripts. The frequency of IL-2 and TGF-β2 transcripts in solid tumours was significantly lower than in the PEC (P = 0.0475). CD4+ or CD8+ T cell lines expressing IFN-γ, IL-2 and IL-10 transcripts were derived in culture with rIL-2 from the TIL of specimens that did not necessarily express these cytokines in the absence of rIL-2. The frequency of cytokine transcripts in T cell lines compared with these same transcripts in the PEC was significantly higher for IFN-γ (P = 0.0005) and lower for TGF-β2 (P = 0.0001). An association was observed between the expression of cytokine transcripts in vivo or by TIL-derived cell lines and functions exhibited by either production of cytokines or in vitro cytotoxicity.
Increased eosinophil activity in acutePlasmodium falciparuminfection—association with cerebral malaria
Authors: Kurtzhals J A L , Reimert C M , Tette E , Dunyo S K , Koram K A , Akanmori B D , Nkrumah F K , Hviid L
Published: March 2003

To assess the eosinophil response to Plasmodium falciparum infection a cohort of initially parasite-free Ghanaian children was followed for 3 months. Seven of nine children who acquired an asymptomatic P. falciparum infection showed increase in eosinophil counts, while a decrease was found in seven of nine children with symptomatic malaria, and no change was observed in 14 children who remained parasite-free. In a hospital-based study, paediatric patients with cerebral malaria (CM), severe anaemia (SA), or uncomplicated malaria (UM) had uniformly low eosinophil counts during the acute illness followed by eosinophilia 30 days after cure. Plasma levels of eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured as indicators of eosinophil activation. In spite of the low eosinophil counts, ECP levels were increased on day 0 and significantly higher in patients with CM (geometric mean (95% confidence interval) 8·5 ng/ml (6·8–10·7 ng/ml)) than in SA (4·7 ng/ml (3·0–7·5 ng/ml)) and UM patients (4·3 ng/ml (3·6–5·3 ng/ml), P < 0·001). A similar pattern was found for EPX. It thus appears that the low eosinophil counts may be due to tissue sequestration and destruction rather than decreased production. The plasma levels of the granule proteins correlated with levels of tumour necrosis factor and soluble IL-2 receptor, implicating inflammatory responses and T cell activation as causes of the eosinophil activation. By contrast, the eosinophil induction did not appear to be part of a Th2-like response. Eosinophil granule proteins may be important in both control of malaria infection and the pathogenesis of severe malaria.
Detection and characterization of antibodies specific to food antigens (gliadin, ovalbumin and β-lactoglobulin) in human serum, saliva, colostrum and milk
Authors: Rumbo M , Chirdo F G , Añón M C , Fossati C A
Published: March 2003

Antibodies against food antigens are usually produced in healthy people. This humoral response can be detected both in serum and secretions. The characterization of this response can be useful for a better understanding of food-related immunological alterations. In this study, IgA and IgG antibodies specific to ovalbumin, β-lactoglobulin or gliadin were measured in serum, saliva, colostrum and milk from 40 healthy breast-feeding women. Specific IgA and IgG to the three antigens were measured by indirect ELISA. Specific IgG levels were highest in serum and very low in the other biological fluids. No correlation between the IgG specific to the different antigens was found. Specific IgA reactivity was found in all the samples analysed. Levels observed were higher in colostrum and milk than in serum and saliva. In spite of being three different unrelated food antigens, a correlation between the levels of specific IgA was found in saliva, colostrum and milk samples of all subjects studied. The specificity of IgA anti-gliadin antibodies from serum, saliva and colostrum was analysed by immunoblotting of SDS–PAGE-separated wheat proteins. Each sample presented a unique pattern of recognition. No common pattern of recognition was found either among the same biological fluids of the different subjects tested, or among the different samples—either serum, colostrum or saliva—of the same individual. Different degrees of specificity to wheat proteins among IgA from colostrum, saliva or serum were observed, suggesting that the local IgA-producing populations are functionally different in the different tissues of the organism.
Aminoguanidine reduces glomerular inducible nitric oxide synthase (iNOS) and transforming growth factor-beta 1 (TGF-β1) mRNA expression and diminishes glomerulosclerosis in NZB/W F1 mice
Authors: Yang C-W , YU C-C , KO Y-C , Huang C-C
Published: March 2003

Over-expression of iNOS is implicated in the pathogenesis of glomerulonephritis in animal models of systemic lupus erythematosus. The aim of this study was to evaluate the effect of aminoguanidine, a selective inhibitor of iNOS, for the protection from glomerulosclerosis in NZB/W F1 mice. Female NZB/W F1 mice (n = 8) were treated with aminoguanidine (1 g/l) in drinking water for 4 months starting at age 2 months before the onset of glomerulonephritis. Controls were age- and sex-matched mice (n = 10) without aminoguanidine treatment. By glomerular microdissection and reverse-transcription competitive polymerase chain reaction, we found that glomerular iNOS/β-actin and TGF-β1/β-actin mRNA ratios were reduced 15.1% (P < 0.05) and 61.3% (P < 0.01), respectively, in aminoguanidine-treated mice. Aminoguanidine significantly reduced the glomerular iNOS staining, urinary nitrite production and degree of glomerulosclerosis. In addition, the glomerular volume and mean glomerular cell number were reduced 33.2% (P < 0.01) and 32.8% (P < 0.01), respectively. Likewise, the urinary proteinuria was also significantly reduced by aminoguanidine. These results indicate that administration of aminoguanidine may reduce the progression of glomerulosclerosis in NZB/W F1 mice, possibly through inhibition of glomerular nitric oxide production.
Effects of anti-IL-4 receptor monoclonal antibody onin vitroT cell cytokine levels: IL-4 production by T cells from non-atopic donors
Authors: Bullens D M A , Kasran A , Peng X , Lorré K , Ceuppens J L
Published: March 2003

IL-4 is a pleiotropic cytokine which is involved in the development of atopic diseases. Only limited data exist on IL-4 production in humans, and the relative contribution to atopy of either unbalanced IL-4 production, or increased IL-4-responsiveness of target cells, is still unknown. The use of a MoAb to the IL-4 receptor α-chain (IL-4Rα) enabled us to demonstrate that IL-4 production in vitro is usually underestimated, due to in vitro consumption, even in cultures of purified T cells. When IL-4 consumption was blocked, it became evident that CD80 and CD86 both provide effective costimulatory signals for high IL-4 production. Moreover, we found that even stimulation with a soluble antigen (tetanus toxoid) induces IL-4 production by T cells from healthy non-atopic donors. Both sets of data imply that IL-4 is not required for IL-4 production by memory and/or effector T cells. Our data further show that endogenous IL-4 activity modulates IL-10 and interferon-gamma production by T cells in opposite directions. The use of this receptor-blocking antibody will thus be helpful for in vitro studies on IL-4 regulation. Consumption of IL-4 by different cell types during in vitro cultures might have interfered with previous attempts to quantify IL-4 production by human T cells.
Complement regulation in innate immunity and the acute-phase response: inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein (CRP)
Authors: Suankratay C , Mold C , Zhang Y , Potempa L A , Lint T F , Gewurz H
Published: March 2003

Mannan-binding lectin (MBL) is an acute-phase protein which activates complement at the level of C4 and C2. We recently reported that the alternative pathway also is required for haemolysis via this ‘lectin pathway’ in human serum. CRP is another acute-phase reactant which activates the classical pathway, but CRP also inhibits the alternative pathway on surfaces to which it binds. Since serum levels of both proteins generally increase with inflammation and tissue necrosis, it was of interest to determine the effect of CRP on cytolysis via the lectin pathway. We report here that although CRP increases binding of C4 to MBL-sensitized erythrocytes, which in turn enhances lectin pathway haemolysis, it inhibits MBL-initiated cytolysis by its ability to inhibit the alternative pathway. This inhibition is characterized by increased binding of complement control protein H and decreased binding of C3 and C5 to the indicator cells, which in turn is attributable to the presence of CRP. Immunodepletion of H leads to greatly enhanced cytolysis via the lectin pathway, and this cytolysis is no longer inhibited by CRP. These results indicate that CRP regulates MBL-initiated cytolysis on surfaces to which both proteins bind by modulating alternative pathway recruitment through H, pointing to CRP as a complement regulatory protein, and suggesting a co-ordinated role for these proteins in complement activation in innate immunity and the acute-phase response.
A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli
Authors: Nagaraju K , Raben N , Merritt G , Loeffler L , Kirk K , Plotz P
Published: March 2003

Muscle is an attractive target for gene therapy and for immunization with DNA vaccines and is also the target of immunological injury in myositis. It is important therefore to understand the immunologic capabilities of muscle cells themselves. In this study, we show that proinflammatory stimuli induce the expression of other cytokines such as IL-6, transforming growth factor-beta (TGF-β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) by muscle cells themselves, as well as the up-regulation of human leucocyte antigen (HLA) class I, class II and intercellular adhesion molecule-1 (ICAM-1). Thus, muscle cells have an inherent ability to express and respond to a variety of cytokines and chemokines. The levels of HLA class I, class II and ICAM-1 in inflamed muscle may be affected by the secreted products of the stimulation.
Immunocytochemical localization of inducible nitric oxide synthase and transforming growth factor-beta (TGF-β) in leprosy lesions
Authors: Khanolkar-Young S , Snowdon D , Lockwood D N J
Published: March 2003

Inducible nitric oxide synthase (iNOS) and TGF-β were localized by immunocytochemistry in skin lesions from patients across the leprosy spectrum, and from patients undergoing reversal reaction. iNOS expression was highest at the tuberculoid pole of the spectrum, and increased during reversal reaction. TGF-β was observed throughout the leprosy spectrum, but was highest at the lepromatous pole. Levels of TGF-β decreased during reversal reaction. Reduced levels of TGF-β may contribute to unregulated inflammatory responses during reactional episodes.
Apoptosis in labial salivary glands from Sjögren's syndrome (SS) patients: comparison with human T lymphotropic virus-I (HTLV-I)-seronegative and -seropositive SS patients
Authors: Nakamura H , Koji T , Tominaga M , Kawakami A , Migita K , Kawabe Y , Nakamura T , Shirabe S , Eguchi K
Published: March 2003

Apoptosis is a type of cell death that occurs during morphogenesis and development of the immune system. One of the mechanisms is mediated through the Fas and Fas ligand (FasL) pathway. To determine the possible involvement of Fas and its ligand in salivary gland destruction, we analysed the appearance of nuclei with DNA fragmentation by using nick end labelling (TUNEL) and the expression of Fas and FasL by immunohistochemistry in labial salivary glands. Furthermore, we compared the features of apoptosis in labial salivary glands between HTLV-I− and HTLV-I+ SS. When the frozen sections of 10 primary SS patients in the absence of anti-HTLV-I antibody were examined, several apoptotic cells were found in the acinar and ductal epithelial cells as well as infiltrated mononuclear cells. Both Fas and FasL were detected in the infiltrated mononuclear cells. Acinar epithelial cells, which are surrounded by FasL+ mononuclear cells, were also double-positive with Fas and FasL, although the expression of FasL was localized at their apical border, suggesting that apoptosis of mononuclear cells was achieved by activation-induced mechanisms through Fas/FasL pathways, and that of acinar epithelial cells was mediated by FasL derived from either acinar epithelial cells themselves or infiltrated mononuclear cells. Interestingly, Fas expression in ductal epithelial cells was localized around the lumen side of the ducts, indicating that FasL secreted from acinar epithelial cells may induce Fas-mediated apoptosis of ductal epithelial cells. We also studied the labial salivary glands from nine SS patients with anti-HTLV-I antibodies. There was no significant difference in the occurrence of apoptotic cells or in the expression of Fas and FasL between HTLV-I+ and HTLV-I− SS patients. It was of note that neither the expression of Fas and FasL nor the presence of apoptotic cells were determined in labial salivary glands from subjects without SS. These findings indicate that Fas-mediated apoptosis in salivary glands could be involved in the pathological manifestations of SS, irrespective of HTLV-I seropositivity.
Increased nitric oxide (NO) production by antigen-presenting dendritic cells is responsible for low allogeneic mixed leucocyte reaction (MLR) in primary biliary cirrhosis (PBC)
Authors: Yamamoto K , MD Fazle Akbar S K , Masumoto T , Onji M
Published: March 2003

The levels of blastogenesis in allogeneic MLR containing T cells from one normal volunteer and irradiated dendritic cells from 29 patients with PBC, 17 patients with chronic hepatitis type C (CH-C) and 22 allogeneic normal controls were compared to see if there is any role of antigen-presenting cells (APC) in the pathogenesis of PBC. The stimulatory capacity of dendritic cells from PBC was significantly lower compared with that of dendritic cells from CH-C (P< 0·05) and normal controls (P < 0·05), which could not be attributable either to the levels of expression of surface molecules, such as HLA-DR and CD86 on dendritic cells, or to the levels of cytokines, such as IL-10 and IL-12. Significantly higher levels of NO were seen in the allogeneic MLR supernatants containing dendritic cells from PBC compared with the supernatants from cultures containing dendritic cells from CH-C (P < 0·001) or normal controls (P < 0·001). Moreover, dendritic cells from PBC produced 10 times more NO compared with dendritic cells from CH-C and normal controls (21·9 ± 2·8 μmversus 1·6 ± 0·3 μm and 1·6 ± 0·3 μm, respectively; P < 0·001). The addition of NG-monomethyl-l-arginine monoacetate (L-NMMA), a known inhibitor of NO in allogeneic MLR containing dendritic cells from PBC, resulted in a significant decrease of NO and increase of blastogenesis. The selective impairment of dendritic cell function, increased production of NO by dendritic cells and restoration of blastogenesis using NO inhibitor in PBC have suggested a role for NO and dysfunction of dendritic cells in the pathogenesis of PBC. This inspires optimism that modulating the function of dendritic cells and controlling NO production, an improved therapeutic approach, might be planned for PBC.
Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-α) production acting on leucocytes resembling immature dendritic cells
Authors: VALLIN H , BLOMBERG S , ALM G V , CEDERBLAD B , RÖNNBLOM L
Published: March 2003

Patients with active SLE often have an ongoing production of IFN-α. We therefore searched for an endogenous IFN-α-inducing factor (IIF) in SLE patients and found that their sera frequently induced production of IFN-α in cultures of peripheral blood mononuclear cells (PBMC) from healthy blood donors, especially when the PBMC were costimulated with the cytokines IFN-α2b and granulocyte-macrophage colony-stimulating factor (GM-CSF). The phenotype of the IFN-α-producing cells (IPC) as determined by flow cytometry corresponded to that of the natural IPC, resembling immature dendritic cells. The IIF activity in SLE sera was sometimes as high as that of a virus and was present especially in patients with active disease and with measurable IFN-α levels in serum. The IIF had an apparent molecular weight of 300–1000 kD and appeared to consist of both immunoglobulin and DNA, possibly being immune complexes. This endogenous IFN-α inducer may be of pathogenic significance, since a reported occasional adverse effect of IFN-α therapy in patients with non-autoimmune disorders is development of anti-dsDNA antibodies and SLE.
Human milk 90K (Mac-2 BP): possible protective effects against acute respiratory infections
Authors: FORNARINI B , IACOBELLI S , TINARI N , NATOLI C , DE MARTINO M , SABATINO G
Published: March 2003

Eighty-six children fed human milk were followed prospectively from birth to 12 months of age to assess the effect of milk 90K, a secreted glycoprotein with immune-stimulatory properties, on development of acute respiratory infections (ARI). The level of human milk 90K was inversely related to episodes of ARI (r = − 0.34; P = 0.001). The average 90K level in human milk fed to children who did not develop ARI was significantly higher than in milk fed to children in whom infection occurred on multiple occasions (156.6 ± 144.8 μg/ml versus 70.9 ± 92.3 μg/ml; P = 0.001). These data suggest that the protective effects of human milk against ARI may be due in part to immune maturation effects by secreted 90K.