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Allergen-specific Th1 cells counteract efferent Th2 cell-dependent bronchial hyperresponsiveness and eosinophilic inflammation partly via IFN-gamma.

https://arctichealth.org/en/permalink/ahliterature15527
Source
J Immunol. 2001 Jan 1;166(1):207-17
Publication Type
Article
Date
Jan-1-2001
Author
T J Huang
P A MacAry
P. Eynott
A. Moussavi
K C Daniel
P W Askenase
D M Kemeny
K F Chung
Author Affiliation
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom.
Source
J Immunol. 2001 Jan 1;166(1):207-17
Date
Jan-1-2001
Language
English
Publication Type
Article
Keywords
Administration, Inhalation
Adoptive Transfer
Allergens - administration & dosage - immunology
Animals
Antibodies, Monoclonal - administration & dosage
Bronchial Hyperreactivity - immunology - pathology - prevention & control
Bronchoalveolar Lavage Fluid - immunology
Cell Line
Epitopes, T-Lymphocyte - administration & dosage - immunology
Inflammation - immunology - pathology - prevention & control
Injections, Intravenous
Interferon Type II - immunology - physiology
Interleukin-4 - antagonists & inhibitors - genetics
Lung - cytology - immunology
Male
Ovalbumin - administration & dosage - immunology
Pulmonary Eosinophilia - immunology - pathology - prevention & control
RNA, Messenger - antagonists & inhibitors
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Th1 Cells - immunology - transplantation
Th2 Cells - immunology - transplantation
Abstract
Th2 T cell immune-driven inflammation plays an important role in allergic asthma. We studied the effect of counterbalancing Th1 T cells in an asthma model in Brown Norway rats that favors Th2 responses. Rats received i.v. transfers of syngeneic allergen-specific Th1 or Th2 cells, 24 h before aerosol exposure to allergen, and were studied 18-24 h later. Adoptive transfer of OVA-specific Th2 cells, but not Th1 cells, and OVA, but not BSA exposure, induced bronchial hyperresponsiveness (BHR) to acetylcholine and eosinophilia in a cell number-dependent manner. Importantly, cotransfer of OVA-specific Th1 cells dose-dependently reversed BHR and bronchoalveolar lavage (BAL) eosinophilia, but not mucosal eosinophilia. OVA-specific Th1 cells transferred alone induced mucosal eosinophilia, but neither BHR nor BAL eosinophilia. Th1 suppression of BHR and BAL eosinophilia was allergen specific, since cotransfer of BSA-specific Th1 cells with the OVA-specific Th2 cells was not inhibitory when OVA aerosol alone was used, but was suppressive with OVA and BSA challenge. Furthermore, recipients of Th1 cells alone had increased gene expression for IFN-gamma in the lungs, while those receiving Th2 cells alone showed increased IL-4 mRNA. Importantly, induction of these Th2 cytokines was inhibited in recipients of combined Th1 and Th2 cells. Anti-IFN-gamma treatment attenuated the down-regulatory effect of Th1 cells. Allergen-specific Th1 cells down-regulate efferent Th2 cytokine-dependent BHR and BAL eosinophilia in an asthma model via mechanisms that depend on IFN-gamma. Therapy designed to control the efferent phase of established asthma by augmenting down-regulatory Th1 counterbalancing mechanisms should be effective.
PubMed ID
11123294 View in PubMed
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Bronchial hyperresponsiveness, epithelial damage, and airway eosinophilia after single and repeated allergen exposure in a rat model of anhydride-induced asthma.

https://arctichealth.org/en/permalink/ahliterature15788
Source
Allergy. 1997 Jul;52(7):739-46
Publication Type
Article
Date
Jul-1997
Author
Z H Cui
M. Sjöstrand
T. Pullerits
P. Andius
B E Skoogh
J. Lötvall
Author Affiliation
Department of Clinical Pharmacology, Göteborg University, Sweden.
Source
Allergy. 1997 Jul;52(7):739-46
Date
Jul-1997
Language
English
Publication Type
Article
Keywords
Animals
Bronchi - immunology - pathology
Bronchial Hyperreactivity - immunology - pathology
Bronchial Provocation Tests
Eosinophilia - immunology
Epithelium - pathology
Humans
Immunoglobulin E - analysis
Immunoglobulin G - analysis
Male
Phthalic Anhydrides - administration & dosage - immunology
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Respiratory Hypersensitivity - immunology - pathology
Vaccination
Abstract
Bronchial hyperresponsiveness (BHR) and damage of the epithelium, as well as eosinophilia in the airway wall, induced by trimellitic anhydride (TMA) in sensitized brown Norway rats were studied. Rats were challenged once or seven times with aerosol of TMA conjugated to rat serum albumin (TMA-RSA) 3 weeks after intradermal TMA sensitization. Airway responsiveness (-log PC300 of acetylcholine i.v.) was measured 24 h after allergen challenge. Epithelial lesion and eosinophil infiltration in the airway walls were quantified under light microscopy, and TMA-specific IgE and IgG in serum were evaluated with ELISA. High levels of TMA-specific IgE and IgG were found in all rats in the sensitized groups compared to nonsensitized groups (P
PubMed ID
9265989 View in PubMed
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CD4+ T cells can induce airway hyperresponsiveness to allergen challenge in the brown norway rat.

https://arctichealth.org/en/permalink/ahliterature57554
Source
Am J Respir Crit Care Med. 1998 Dec;158(6):1863-70
Publication Type
Article
Date
Dec-1998
Author
H. Mishima
M. Hojo
A. Watanabe
Q A Hamid
J G Martin
Author Affiliation
Meakins-Christie Laboratories, Royal Victoria Hospital, McGill University, and the Respiratory Health Network of Centres of Excellence, Montreal, Quebec, Canada.
Source
Am J Respir Crit Care Med. 1998 Dec;158(6):1863-70
Date
Dec-1998
Language
English
Publication Type
Article
Keywords
Aerosols
Allergens - immunology
Animals
Bronchial Hyperreactivity - immunology
Bronchial Provocation Tests
Bronchoalveolar Lavage Fluid - chemistry - immunology
Bronchoconstrictor Agents - diagnostic use
CD4-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - immunology
Cattle
Comparative Study
Eosinophilia - immunology
Gene Expression Regulation
Immunization
Immunoglobulin E - immunology
In Situ Hybridization
Interferon Type II - genetics - immunology
Interleukin-5 - genetics - immunology
Male
Methacholine Chloride - diagnostic use
Ovalbumin - immunology
Proteins - analysis
RNA, Messenger - genetics
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Serum Albumin, Bovine - immunology
Time Factors
Abstract
Airway hyperresponsiveness to inhalational challenge with methacholine (MCh) develops by 32 h after allergen challenge of actively sensitized BN rats. To test the hypothesis that CD4+ T cells mediate allergen-induced hyperresponsiveness independent of IgE-mediated mechanisms, we administered CD4+ T cells, CD8+ T cells, and a mixture of CD4+ and CD8+ T cells (total T cells) isolated from the cervical lymph nodes of rats sensitized with ovalbumin (OA) to naive BN rats that underwent aerosol challenge with either OA or bovine serum albumin (BSA) 2 d later. Responsiveness to MCh was measured 2 d before transfer of T cells and 32 h after challenge with OA or BSA. Airway responsiveness increased significantly in recipients of CD4+ T cells after OA challenge, but not in any other of the treatment groups. Analysis of bronchoalveolar lavage (BAL) cells for major basic protein expression by immunostaining showed eosinophilia in OA-challenged CD4+ and total T-cell recipients. Cells retrieved by bronchoalveolar lavage showed increased expression of IL-5 mRNA (in situ hybridization) in CD4+ T cell recipients after OA challenge compared with other groups. Interferon-gamma mRNA was expressed to the greatest extent in CD8+ recipients, but it was elevated in both OA- and BSA-challenged animals. We conclude that CD4+ T cells can induce airway hyperresponsiveness after inhalational challenge with allergen and this is associated with IL-5 production and eosinophilia. CD8+ T cells may have a negative regulatory effect on responsiveness, possibly mediated by interferon-gamma.
PubMed ID
9847279 View in PubMed
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The effects of CD8+gammadelta T cells on late allergic airway responses and airway inflammation in rats.

https://arctichealth.org/en/permalink/ahliterature57418
Source
J Allergy Clin Immunol. 2003 Sep;112(3):547-55
Publication Type
Article
Date
Sep-2003
Author
Susumu Isogai
Alexandra Rubin
Karim Maghni
David Ramos-Barbon
Rame Taha
Yasuyuki Yoshizawa
Qutayba Hamid
James G Martin
Author Affiliation
Meakins Christie Laboratories, Department of Medicine, McGill University, 3623 St Urbain, Montreal, Quebec, Canada H2X 2P2.
Source
J Allergy Clin Immunol. 2003 Sep;112(3):547-55
Date
Sep-2003
Language
English
Publication Type
Article
Keywords
Adoptive Transfer
Allergens - administration & dosage
Animals
CD8-Positive T-Lymphocytes - immunology
Cytokines - biosynthesis - genetics
Eosinophilia - immunology
Immunoglobulin E - blood
Interferon Type II - biosynthesis - genetics
Interleukin-4 - biosynthesis - genetics
Male
Models, Immunological
Ovalbumin - administration & dosage - immunology
RNA, Messenger - genetics - metabolism
Rats
Rats, Inbred BN
Receptors, Antigen, T-Cell, gamma-delta - metabolism
Research Support, Non-U.S. Gov't
Respiratory Hypersensitivity - etiology - immunology
T-Lymphocyte Subsets - immunology
Abstract
BACKGROUND: Gamma-delta (gammadelta) T cells regulate immune responses to foreign protein at mucosal surfaces. Whether they can modify allergen-induced early (EAR) and late airway responses (LAR) is unknown. OBJECTIVE: We have tested the hypothesis that the CD8+ subtype of gammadelta T cells decreases allergen-induced LAR and airway eosinophilia in the rat. METHODS: Brown Norway rats were administered, intraperitoneally, 3.5 x 10(4) lymph node CD8+gammadelta T cells from naive or sensitized rats. The recipients were sensitized to ovalbumin (OVA) in Al(OH)(3) 3 days after cell transfer and challenged with aerosolized OVA 14 days later. Serum IgE was measured before allergen challenge. After challenge, lung resistance was monitored for 8 hours and then bronchoalveolar lavage (BAL) was analyzed for eosinophil major basic protein (MBP), IL-4, IL-5, IL-13, and IFN-gamma messenger RNA-expressing cells. RESULTS: gammadelta T cells from naive donors significantly decreased LAR in OVA-challenged sensitized rats, whereas MBP(+) eosinophils were decreased by both gammadelta T cells from naive and sensitized donors. EAR and serum IgE levels were unchanged. The expression of IL-4, IL-5, and IL-13 by BAL cells of gammadelta T cell recipients was attenuated compared with OVA-challenged controls. This was accompanied by an increase in the expression of IFN-gamma. CONCLUSIONS: Our results are consistent with a suppressive role of CD8+gammadelta T cells on allergic airway responses. However, only gammadelta T cells from naive donors inhibit LAR.
PubMed ID
13679814 View in PubMed
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IFN-gamma secretion by CD8T cells inhibits allergen-induced airway eosinophilia but not late airway responses.

https://arctichealth.org/en/permalink/ahliterature15380
Source
J Allergy Clin Immunol. 2002 May;109(5):803-9
Publication Type
Article
Date
May-2002
Author
Masaru Suzuki
Karim Maghni
Sophie Molet
Ayako Shimbara
Qutayba A Hamid
James G Martin
Author Affiliation
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Source
J Allergy Clin Immunol. 2002 May;109(5):803-9
Date
May-2002
Language
English
Publication Type
Article
Keywords
Adoptive Transfer
Allergens - immunology
Animals
Bronchi - immunology
Bronchial Hyperreactivity - immunology - physiopathology
Bronchitis - immunology - pathology
Bronchoalveolar Lavage Fluid - chemistry - cytology
CD8-Positive T-Lymphocytes - drug effects - metabolism - transplantation
Eosinophilia - immunology - prevention & control
Interferon Type II - physiology
Male
Oligonucleotides, Antisense - pharmacology
Ovalbumin - immunology
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Time Factors
Abstract
BACKGROUND: CD8+T cells can suppress allergen-induced late airway responses (LARs) and airway inflammation. OBJECTIVE: To test the hypothesis that the suppression of LARs and airway eosinophilia by CD8+T cells is IFN-gamma mediated, we tested the effects of adoptively transferred CD8+T cells, in which IFN-gamma synthesis was inhibited by an antisense (AS) oligodeoxynucleotide (ODN), on the airway responses of a rat model of allergic asthma. METHODS: CD8+T cells were harvested from the cervical lymph nodes of ovalbumin (OVA)-sensitized Brown Norway rats for administration to other actively sensitized syngeneic rats. CD8+T cells (2 x 10(6)) were incubated for 6 hours with 2 micromol/L AS ODN or sense ODN and were injected intraperitoneally into recipients; inhibition of IFN-gamma expression in vitro by AS ODN was shown by means of flow cytometry. Two days later, rats were challenged with aerosolized OVA. RESULTS: OVA-induced LAR and bronchoalveolar lavage (BAL) fluid eosinophilia were suppressed by sense ODN-treated CD8+T cells. IFN-gamma expression in BAL cells was elevated in these animals. IFN-gamma expression in BAL cells was at control levels in recipients of AS ODN-treated CD8+ cells, confirming the success of the AS treatment in vivo. BAL eosinophilia was also largely restored in the AS ODN treatment group. In contrast, the CD8+T cell-induced suppression of the LAR was not significantly affected by AS ODN pretreatment. CONCLUSIONS: These results indicate that CD8+T cells inhibit airway eosinophilia through secretion of IFN-gamma but may suppress the LAR by means of other mechanisms.
PubMed ID
11994704 View in PubMed
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IgE concentrations measured by PRIST in serum of healthy adults and in patients with respiratory allergy. A diagnostic approach.

https://arctichealth.org/en/permalink/ahliterature16236
Source
Allergy. 1981 Nov;36(8):537-47
Publication Type
Article
Date
Nov-1981
Author
O. Zetterström
S G Johansson
Source
Allergy. 1981 Nov;36(8):537-47
Date
Nov-1981
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Allergens - immunology
Asthma - immunology
Bronchial Provocation Tests
Eczema - epidemiology
Eosinophilia - immunology
Female
Health Surveys
Humans
Hypersensitivity, Immediate - diagnosis - epidemiology - genetics
Immunoglobulin E - biosynthesis
Male
Middle Aged
Nasal Provocation Tests
Radioallergosorbent Test
Radioimmunosorbent Test
Respiratory Hypersensitivity - diagnosis - epidemiology - immunology
Rhinitis - epidemiology
Skin Tests
Sweden
Urticaria - epidemiology
Abstract
In order to establish reference values for total serum IgE in an adult non-atopic population, 175 individuals, 17-85 years of age, were investigated. The usefulness of a sensitive method (PRIST) for serum IgE determinations in discriminating atopy from non-atopic conditions in allergological routine diagnosis was elucidated by investigating 445 patients with symptoms of asthma, rhinitis, urticaria and eczema. Comparisons were made with case histories, in vivo tests and circulating IgE antibodies. The geometric mean for serum IgE in the reference material was 13.2 kU/l with a 2 SD range of 1.53 to 114 kU/l. No significant difference between age groups or sexes was observed. In patients classified as non-atopic and pronounced atopic, the geometric mean values for IgE were 40, 123 and 458 kU/l respectively. The IgE level correlated with number of allergens positive in RAST and with skin test results. It is concluded that IgE determinations are of great help in discriminating atopic conditions from other diseases with similar symptoms. A serum IgE value above 100 kU/l in a patient is strong evidence for the presence of an atopic disease while a value below 20 kU/l indicates that the symptoms are due to intrinsic or infectious disease.
PubMed ID
7337200 View in PubMed
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Inhibition of antigen-induced pulmonary eosinophilia and neutrophilia by selective inhibitors of phosphodiesterase types 3 or 4 in Brown Norway rats.

https://arctichealth.org/en/permalink/ahliterature15919
Source
Pulm Pharmacol. 1995 Apr-Jun;8(2-3):83-9
Publication Type
Article
Author
R E Howell
L P Jenkins
L E Fielding
D. Grimes
Author Affiliation
Inflammatory Diseases Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
Source
Pulm Pharmacol. 1995 Apr-Jun;8(2-3):83-9
Language
English
Publication Type
Article
Keywords
Aminophylline - pharmacology
Animals
Leukocytosis - prevention & control
Male
Neutrophils - drug effects
Phosphodiesterase Inhibitors - pharmacology
Pulmonary Eosinophilia - immunology - prevention & control
Purinones - pharmacology
Pyrrolidinones - pharmacology
Rats
Rolipram
Abstract
Rolipram, a phosphodiesterase type 4 (PDE4)-selective inhibitor, has been demonstrated to inhibit antigen-induced pulmonary eosinophilia in guinea pigs and monkeys, suggesting that PDE4-selective inhibitors could be useful for treating asthma. Although the rat is used extensively in preclinical drug development, a pulmonary antiinflammatory effect of PDE4 inhibition has not been demonstrated in this species. Therefore, we examined the effects of rolipram, CI-930 (PDE3-selective inhibitor), zaprinast (PDE5-selective inhibitor) and aminophylline on antigen-induced pulmonary inflammatory cell influx in Brown Norway rats. Two weeks after sensitization rats were exposed to aerosolized ovalbumin and 24 h later bronchoalveolar lavage (BAL) was performed for determinations of total cell counts and cell type differentials. The resulting 10-fold increase in total cell counts was due primarily to an increase in eosinophils (from 0.06 to 11.0 x 10(6)) and neutrophils (from 0.02 to 12 x 10(6)). Rolipram, CI-930 and aminophylline, given p.o. before and after antigen challenge, each completely inhibited eosinophil influx, with B.I.D. ED50 values of 0.5, 0.4 and 39 mg/kg, respectively. Rolipram, CI-930 and aminophylline each completely inhibited neutrophil influx as well, with B.I.D. ED50 values of 0.1, 0.5 and 20 mg/kg, respectively. Denbufylline and milrinone (10 mg/kg p.o.) also inhibited eosinophil and neutrophil influx, consistent with PDE4 and PDE3 inhibition as the mechanisms of action of rolipram and CI-930, respectively. In contrast, zaprinast was inactive at 0.3-30 mg/kg. However, the beta2 agonist salbutamol greatly inhibited antigen-induced pulmonary eosinophilia and neutrophilia, with p.o. B.I.D. ED50 values of 2.1 and 2.3 mg/kg, respectively, indicating that drugs which increase intracellular cAMP levels by one of several mechanisms can inhibit antigen-induced pulmonary inflammation in rats. In conclusion, these results demonstrate that PDE4 inhibitors produce pulmonary antiinflammatory effects in rats. Furthermore, these results suggest that PDE3 inhibitors also can produce pulmonary antiinflammatory effects in vivo.
PubMed ID
8820246 View in PubMed
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Mast-cell activation augments the late phase reaction in experimental immune-mediated blepharoconjunctivitis.

https://arctichealth.org/en/permalink/ahliterature50704
Source
Graefes Arch Clin Exp Ophthalmol. 2003 May;241(5):394-402
Publication Type
Article
Date
May-2003
Author
Akemi Ozaki
Atsuki Fukushima
Kazuyo Fukata
Hisayuki Ueno
Author Affiliation
Laboratory of Immunology, Department of Ophthalmology, Kochi Medical School, Kohasu, Oko-cho, 783-8505 Nankoku-city, Japan.
Source
Graefes Arch Clin Exp Ophthalmol. 2003 May;241(5):394-402
Date
May-2003
Language
English
Publication Type
Article
Keywords
Animals
Blepharitis - chemically induced - immunology - pathology
Cell Movement
Conjunctivitis, Allergic - chemically induced - immunology - pathology
Enzyme-Linked Immunosorbent Assay
Eosinophilia - immunology
Eosinophils - physiology
Flow Cytometry
Hypersensitivity, Delayed - immunology - pathology
Lymphocyte Activation
Male
Mast Cells - physiology
Ovalbumin - immunology
RANTES - metabolism
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes - immunology
p-Methoxy-N-methylphenethylamine
Abstract
BACKGROUND: How the early phase allergic reaction affects the late phase reaction remains unclear. We examined this issue with an experimental model of allergic conjunctivitis that permits the two reactions to be disconnected from each other. METHODS: Experimental immune-mediated blepharoconjunctivitis (EC) was initiated in Brown Norway rats by transferring ovalbumin (OVA)-specific T cells and then challenging with OVA-containing eye drops. To induce early phase reaction, a mast-cell activator, C48/80, was challenged together with or without OVA. Rats were evaluated clinically and eyes were harvested for histologic examination and for evaluation of chemokine expression by reverse-transcriptase PCR. RESULTS: The rats challenged with OVA alone developed the T-cell-mediated late phase reaction histologically, but not clinically, in the absence of early phase reaction. While rats challenged with C48/80 with or without OVA exhibited clinical signs of the early phase reaction, the clinical late phase reaction was observed only in the OVA+C48/80 group. Eosinophilic infiltration into the conjunctiva during the late phase reaction of the OVA+C48/80 group markedly exceeded that of rats challenged with either OVA or C48/80 alone. RANTES (regulated on activation, normal T-cell expressed and secreted), an eosinophil attractant, was expressed both in the OVA+C48/80 and OVA groups, while eotaxin was expressed at equivalent levels in all three groups. CONCLUSION: The mast-cell-mediated early phase reaction potentiates the T-cell-mediated late phase reaction, and RANTES is involved in eosinophilic infiltration induced by antigen-specific T cells. Other molecules induced by allergen-specific T cells activated in an as yet unknown manner by the mast cells may be responsible for the infiltration of eosinophils.
PubMed ID
12682842 View in PubMed
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Outbreak of trichinellosis associated with consumption of game meat in West Greenland.

https://arctichealth.org/en/permalink/ahliterature5974
Source
Vet Parasitol. 2005 Sep 5;132(1-2):131-6
Publication Type
Article
Date
Sep-5-2005
Author
Lone Nukâraq Møller
Eskild Petersen
Christian M O Kapel
Mads Melbye
Anders Koch
Author Affiliation
Danish Centre for Experimental Parasitology, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark. lnm@kvl.dk
Source
Vet Parasitol. 2005 Sep 5;132(1-2):131-6
Date
Sep-5-2005
Language
English
Publication Type
Article
Keywords
Adult
Animals
Antibodies, Helminth - blood
Antigens, Helminth - chemistry
Blotting, Western
Child
Disease Outbreaks
Enzyme-Linked Immunosorbent Assay
Eosinophilia - immunology
Female
Food Parasitology
Greenland - epidemiology
Helminth Proteins - chemistry
Hexoses - chemistry
Humans
Male
Meat - parasitology
Middle Aged
Trichinella
Trichinosis - diagnosis - epidemiology - parasitology
Walruses - parasitology
Abstract
The Inuit population of the Arctic has always been at risk of acquiring trichinellosis and severe outbreaks have been recorded in Alaska and Canada. In West Greenland, a number of large outbreaks took place during the 1940s and 1950s; they involved total 420 cases including 37 deaths. Since then only sporadic cases have been reported. Here, we describe an outbreak of infection with Trichinella spp. after consumption of infected meat presumably from walrus or polar bear caught in western Greenland. Six persons who had eaten of the walrus and polar bear meat were two males and four females, age range 6--47 years. Using ELISA and Western blot analysis (Trichinella-specific IgG antibodies against excreted/secreted antigen and synthetic tyvelose antigen, respectively) four of these persons were found to be sero-positive for Trichinella antibodies, with three of these having clinical symptoms compatible with trichinellosis. On re-test, 12--14 months later one of the two sero-negative persons had sero-converted, probably due to a new, unrelated infection. This study demonstrates that acquiring Trichinella from the consumption of marine mammals remains a possibility in Greenland, and that cases may go undetected. Trichinellosis in Greenland can be prevented by the implementation of public health measures.
PubMed ID
16023294 View in PubMed
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Proteasome inhibition: A novel mechanism to combat asthma.

https://arctichealth.org/en/permalink/ahliterature15647
Source
J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):294-300
Publication Type
Article
Date
Aug-1999
Author
P J Elliott
C S Pien
T A McCormack
I D Chapman
J. Adams
Author Affiliation
ProScript, Inc, Cambridge, MA 02319, USA.
Source
J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):294-300
Date
Aug-1999
Language
English
Publication Type
Article
Keywords
Animals
Asthma - physiopathology - prevention & control
Cysteine Endopeptidases - drug effects
Cysteine Proteinase Inhibitors - physiology
Dexamethasone - adverse effects
Hypersensitivity, Delayed - chemically induced
Lactones - chemistry - pharmacology
Male
Mice
Mice, Inbred BALB C
Multienzyme Complexes - drug effects
Proteasome Endopeptidase Complex
Pulmonary Eosinophilia - immunology - physiopathology - prevention & control
Rats
Rats, Inbred BN
Structure-Activity Relationship
Abstract
BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is a critical transcription factor required for the regulation of many genes involved in inflammatory responses to noxious stimuli. On activation, NF-kappaB induces the transcription of numerous proinflammatory cytokines, enzymes, and cellular adhesion molecules. Blockade of the proteasome with selective inhibitors attenuates the effects of NF-kappaB, leading to suppression of the inflammatory response. OBJECTIVE: We sought to determine whether proteasome inhibitors would be active in a model of asthma. METHODS: The mouse delayed-type hypersensitivity model was used to screen a panel of compounds for in vivo activity. The proteasome inhibitor, PS-519, was shown to be the most active in this model and was selected for further development. Allergen-induced pulmonary eosinophilia in Brown Norway rats was used subsequently to determine anti-inflammatory activity in an animal model. RESULTS: Direct administration of PS-519 into the lungs significantly reduced leukocyte numbers, particularly the selective increase in eosinophils. Because steroids are the mainstay anti-inflammatory therapy in asthma, and data is available to suggest their possible interaction to suppress the activation of NF-kappaB, rats were also treated by inhalation with combinations of a steroid and the proteasome inhibitor. In both the delayed-type hypersensitivity and the animal eosinophil model, low doses of proteasome inhibitors were shown to be effective when given with low doses of steroids. CONCLUSION: Taken together, the present data suggest that proteasome inhibition may represent a novel strategy for the treatment of inflammatory lung diseases such as asthma.
PubMed ID
10452747 View in PubMed
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12 records – page 1 of 2.