Publications by authors named "Geir Hetland"

25 Publications

  • Page 1 of 1

HLA class I depletion by citric acid, and irradiation of apheresis platelets for transfusion of refractory patients.

Transfusion 2021 04 13;61(4):1222-1234. Epub 2021 Feb 13.

Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.

Background: Patients can form antibodies to foreign human leukocyte antigen (HLA) Class I antigens after exposure to allogeneic cells. These anti-HLA class I antibodies can bind transfused platelets (PLTs) and mediate their destruction, thus leading to PLT refractoriness. Patients with PLT refractoriness need HLA-matched PLTs, which require expensive HLA typing of donors, antibody analyses of patient sera and/or crossmatching. An alternative approach is to reduce PLT HLA Class I expression using a brief incubation in citric acid on ice at low pH.

Methods And Materials: Apheresis PLT concentrates were depleted of HLA Class I complexes by 5 minutes incubation in ice-cold citric acid, at pH 3.0. Surface expression of HLA Class I complexes, CD62P, CD63, phosphatidylserine, and complement factor C3c was analyzed by flow cytometry. PLT functionality was tested by thromboelastography (TEG).

Results: Acid treatment reduced the expression of HLA Class I complexes by 71% and potential for C3c binding by 11.5-fold compared to untreated PLTs. Acid-treated PLTs were significantly more activated than untreated PLTs, but irrespective of this increase in steady-state activation, CD62P and CD63 were strongly upregulated on both acid-treated and untreated PLTs after stimulation with thrombin receptor agonist peptide. Acid treatment did not induce apoptosis over time. X-ray irradiation did not significantly influence the expression of HLA Class I complexes, CD62P, CD63, and TEG variables on acid treated PLTs.

Conclusion: The relatively simple acid stripping method can be used with irradiated apheresis PLTs and may prevent transfusion-associated HLA sensitization and overcome PLT refractoriness.
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http://dx.doi.org/10.1111/trf.16282DOI Listing
April 2021

Can medicinal mushrooms have prophylactic or therapeutic effect against COVID-19 and its pneumonic superinfection and complicating inflammation?

Scand J Immunol 2021 Jan 29;93(1):e12937. Epub 2020 Jul 29.

Norwegian Institute of Public Health, Oslo, Norway.

Medicinal mushrooms have documented effects against different diseases, including infections and inflammatory disorders. The related Basidiomycota Agaricus blazei Murill (AbM), Hericium erinaceus (HE), and Grifola frondosa (GF) have been shown to exert antimicrobial activity against viral agents, Gram-positive and Gram-negative bacteria, and parasites in vitro and in vivo. Since the mechanism is immunomodulatory and not antibiotical, the mushrooms should be active against multi-drug resistant microbes as well. Moreover, since these Basidiomycota also have anti-inflammatory properties, they may be suited for treatment of the severe lung inflammation that often follows COVID-19 infection. An AbM-based mushroom extract (Andosan™), also containing HE and GF, has been shown to significantly reduce bacteraemia and increase survival in mice with pneumococcal sepsis, and to improve symptoms and quality of life in IBD patients via an anti-inflammatory effect. Hence, such mushroom extracts could have prophylactic or therapeutic effect against the pneumonic superinfection and severe lung inflammation that often complicates COVID-19 infection. Here, we review antimicrobial and anti-inflammatory properties of AbM, HE and GF mushrooms, which could be used for the battle against COVID-19.
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http://dx.doi.org/10.1111/sji.12937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404338PMC
January 2021

Antitumor, Anti-Inflammatory and Antiallergic Effects of Mushroom Extract and the Related Medicinal Basidiomycetes Mushrooms, and : A Review of Preclinical and Clinical Studies.

Nutrients 2020 May 8;12(5). Epub 2020 May 8.

Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.

Since the 1980s, medicinal effects have been documented in scientific studies with the related mushrooms Murill (AbM), (HE) and (GF) from Brazilian and Eastern traditional medicine. Special focus has been on their antitumor effects, but the mushrooms' anti-inflammatory and antiallergic properties have also been investigated. The antitumor mechanisms were either direct tumor attack, e.g., apoptosis and metastatic suppression, or indirect defense, e.g., inhibited tumor neovascularization and T helper cell (Th) 1 immune response. The anti-inflammatory mechanisms were a reduction in proinflammatory cytokines, oxidative stress and changed gut microbiota, and the antiallergic mechanism was amelioration of a skewed Th1/Th2 balance. Since a predominant Th2 milieu is also found in cancer, which quite often is caused by a local chronic inflammation, the three conditions-tumor, inflammation and allergy-seem to be linked. Further mechanisms for HE were increased nerve and beneficial gut microbiota growth, and oxidative stress regulation. The medicinal mushrooms AbM, HE and GF appear to be safe, and can, in fact, increase longevity in animal models, possibly due to reduced tumorigenesis and oxidation. This article reviews preclinical and clinical findings with these mushrooms and the mechanisms behind them.
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http://dx.doi.org/10.3390/nu12051339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285126PMC
May 2020

NETs analysed by novel calprotectin-based assays in blood donors and patients with multiple myeloma or rheumatoid arthritis: A pilot study.

Scand J Immunol 2020 May 4;91(5):e12870. Epub 2020 Mar 4.

Department of Immunology and Transfusion Medicine, Oslo University Hospital (OUH), Oslo, Norway.

Two novel enzyme-linked immunosorbent assays (ELISAs), designed to detect complexes containing DNA, leucocyte calprotectin and S100A12 proteins, were generated for improved specificity and rapid measurement of neutrophil extracellular traps (NETs). The assays were applied on plasma and serum samples from blood donors for establishment of reference values, and from patients with multiple myeloma (MM) or rheumatoid arthritis (RA) in order to examine putatively increased values in the two different inflammatory conditions. Although NETs were hardly detectable in healthy individuals, NET levels were as expected highly and statistically significantly increased in RA patients. The detection of statistically significantly increased NET levels in MM is a novel finding.
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http://dx.doi.org/10.1111/sji.12870DOI Listing
May 2020

-Based Mushroom Extract Supplementation to Birch Allergic Blood Donors: A Randomized Clinical Trial.

Nutrients 2019 Oct 2;11(10). Epub 2019 Oct 2.

Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0407 Oslo, Norway.

Since Murill (AbM) extract reduced specific IgE and ameliorated a skewed Th1/Th2 balance in a mouse allergy model, it was tested in blood donors with self-reported, IgE-positive, birch pollen allergy and/or asthma. Sixty recruited donors were randomized in a placebo-controlled, double-blinded study with pre-seasonal, 7-week, oral supplementation with the AbM-based extract Andosan. Before and after the pollen season, questionnaires were answered for allergic rhino-conjunctivitis, asthma, and medication; serum IgE was measured, and Bet v 1-induced basophil activation was determined by CD63 expression. The reported general allergy and asthma symptoms and medication were significantly reduced in the AbM compared to the placebo group during pollen season. During the season, there was significant reduction in specific IgE anti-Bet v 1 and anti-t3 (birch pollen extract) levels in the AbM compared with the placebo group. While the maximal allergen concentrations needed for eliciting basophil activation before the season, changed significantly in the placebo group to lower concentrations (i.e., enhanced sensitization) after the season, these concentrations remained similar in the Andosan AbM extract group. Hence, the prophylactic effect of oral supplementation before the season with the AbM-based Andosan extract on aeroallergen-induced allergy was associated with reduced specific IgE levels during the season and basophils becoming less sensitive to allergen activation.
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http://dx.doi.org/10.3390/nu11102339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836217PMC
October 2019

IgE-sensitization to food and inhalant allergens in IBD patients compared with normal blood donors at Oslo University Hospital, Norway.

Scand J Gastroenterol 2019 Sep 14;54(9):1107-1110. Epub 2019 Sep 14.

Institute of Clinical Medicine, University of Oslo , Oslo , Norway.

Crohn's disease (CD) and ulcerative colitis (UC) have been regarded as autoimmune Th-1/Th-17- and Th-2-associated conditions, respectively. The aim of the study was to examine possible differences in allergen sensitization between these diseases and relative to normal blood donors (BD). Plasma from 29 UC and 37 CD patients with moderate disease activity and 100 healthy age- and gender-matched BD, were analyzed for specific IgE to 22 food- and 28 inhalation allergens using EUROLINE atopy screen. There was significantly higher proportion of allergen sensitized patients in UC compared to BD. Corresponding mean percentages for UC, CD and BD were 8.5, 8.9 ( = .2) and 5.9 ( = .04). There was no intergroup difference in sensitization to food allergens. Most prominent result was the double level of sensitization to inhalants in CD (15%) compared to BD (8%) ( = .03). Overall highest levels of sensitization to inhalants were for grass pollens. Interestingly, the number of allergens ( = 50) the subjects were sensitized to, was significantly lower among UC ( = 20; 40%) ( = .0005) than CD ( = 31; 62%) and BD ( = 38; 76%). The percentage of individuals sensitized to inhalants in CD and to inhalants and foods in UC, were higher than corresponding results in BD. However, whereas allergen positive reactions in CD were comparable to those in BD, they were reduced in UC because of the few UC reactions to food allergens. This contrasts previous data and the study also points to sensitization to inhalants as a potential factor in the complex pathogenesis of IBD.
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http://dx.doi.org/10.1080/00365521.2019.1663445DOI Listing
September 2019

Cytotoxic Effect on Human Myeloma Cells and Leukemic Cells by the Murill Based Mushroom Extract, Andosan™.

Biomed Res Int 2017 7;2017:2059825. Epub 2017 Nov 7.

Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, 0318 Oslo, Norway.

Murill is an edible mushroom of the Basidiomycetes family, which has been found to contain a number of compounds with antitumor properties, such as proteoglycans and ergosterol. In the present investigation, we show that the commercial mushroom product Andosan, which contains 82.4% Murill, together with medicinal mushrooms (14.7%) and (2.9%), has a cytotoxic effect on primary myeloma cells, other myeloma cell lines, and leukemia cell lines Although the exact content and hence the mechanisms of action of the Andosan extract are unknown, we have found in this investigation indications of cell cycle arrest when myeloma cell lines are cultivated with Andosan. This may be one of the possible explanations for the cytotoxic effects of Andosan.
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http://dx.doi.org/10.1155/2017/2059825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697368PMC
July 2018

The Agaricus blazei-Based Mushroom Extract, Andosan™, Protects against Intestinal Tumorigenesis in the A/J Min/+ Mouse.

PLoS One 2016 21;11(12):e0167754. Epub 2016 Dec 21.

Norwegian University of Life Sciences, Department of Food Safety and Infection Biology, Oslo, Norway.

Background: The novel A/J Min/+ mouse, which is a model for human Familial Adenomatous Polyposis (FAP), develops spontaneously multiple adenocarcinomas in the colon as well as in the small intestine. Agaricus blazei Murill (AbM) is an edible Basidiomycetes mushroom that has been used in traditional medicine against cancer and other diseases. The mushroom contains immunomodulating β-glucans and is shown to have antitumor effects in murine cancer models. Andosan™ is a water extract based on AbM (82%), but it also contains the medicinal Basidiomycetes mushrooms Hericeum erinaceus and Grifola frondosa.

Methods And Findings: Tap water with 10% Andosan™ was provided as the only drinking water for 15 or 22 weeks to A/J Min/+ mice and A/J wild-type mice (one single-nucleotide polymorphism (SNP) difference), which then were exsanguinated and their intestines preserved in formaldehyde and the serum frozen. The intestines were examined blindly by microscopy and also stained for the tumor-associated protease, legumain. Serum cytokines (pro- and anti-inflammatory, Th1-, Th2 -and Th17 type) were measured by Luminex multiplex analysis. Andosan™ treated A/J Min/+ mice had a significantly lower number of adenocarcinomas in the intestines, as well as a 60% significantly reduced intestinal tumor load (number of tumors x size) compared to control. There was also reduced legumain expression in intestines from Andosan™ treated animals. Moreover, Andosan™ had a significant cytotoxic effect correlating with apoptosis on the human cancer colon cell line, Caco-2, in vitro. When examining serum from both A/J Min/+ and wild type mice, there was a significant increase in anti-tumor Th1 type and pro-inflammatory cytokines in the Andosan™ treated mice.

Conclusions: The results from this mouse model for colorectal cancer shows significant protection of orally administered Andosan™ against development of intestinal cancer. This is supported by the finding of less legumain in intestines of Andosan™ treated mice and increased systemic Th1 cytokine response. The mechanism is probably both immuno-modulatory and growth inhibition of tumor cells by induction of apoptosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167754PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5176274PMC
July 2017

Effect of the Medicinal Agaricus blazei Murill-Based Mushroom Extract, AndoSanTM, on Symptoms, Fatigue and Quality of Life in Patients with Crohn's Disease in a Randomized Single-Blinded Placebo Controlled Study.

PLoS One 2016 14;11(7):e0159288. Epub 2016 Jul 14.

Department of Gastrointestinal and Pediatric Surgery, Oslo University Hospital, Ullevål, Oslo, Norway.

Background: Ingestion of AndoSanTM, based on the mushroom Agaricus blazei Murill, has previously shown an anti-inflammatory effect through reduction of pro-inflammatory cytokines in healthy individuals and patients with Crohn's disease (CD). In this randomized single-blinded placebo-controlled study we examined whether intake of AndoSanTM also resulted in clinical effects.

Methods And Findings: 50 patients with symptomatic CD were randomized for oral daily consumption of AndoSanTM or placebo for a 21-day experimental period, in this per-protocol study. Patients reported validated scores for symptoms, fatigue and health related quality of life (HRQoL) at days 0, 14 and 21. Fecal calprotectin and general blood parameters were also analyzed. In the AndoSanTM group (n = 25) symptoms improved from baseline (day 0) to days 14 and 21, with respective mean scores (95% CI) of 5.52 (4.64-6.40), 4.48 (3.69-5.27) and 4.08 (3.22-4.94) (p<0,001). We found significant improvements in symptom score for both genders in the AndoSanTM group, and no significant changes in the placebo (n = 25) group. There were however no significant differences between the groups (p = 0.106), although a marginal effect in symptom score for men (p = 0.054). There were comparable improvements in physical, mental and total fatigue for both groups. HRQoL versus baseline were at day 21 improved for bodily pain and vitality in the AndoSanTM group and for vitality and social functioning in the placebo group. No crucial changes in general blood samples and fecal calprotectin were detected.

Conclusions: The results from this single-blinded randomized clinical trial shows significant improvement on symptoms, for both genders, in the AndoSanTM group, but no significant differences between the study groups. The results on fatigue, HRQoL, fecal calprotectin and blood samples were quite similar compared with placebo. The patients did not report any harms or unintended effects of AndoSanTM. CD patients with mild to moderate symptoms may have beneficiary effects of AndoSanTM as a safe supplement in addition to conventional medication.

Trial Registration: ClinicalTrials.gov NCT01496053.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944955PMC
July 2017

Effect of a Medicinal Agaricus blazei Murill-Based Mushroom Extract, AndoSan™, on Symptoms, Fatigue and Quality of Life in Patients with Ulcerative Colitis in a Randomized Single-Blinded Placebo Controlled Study.

PLoS One 2016 2;11(3):e0150191. Epub 2016 Mar 2.

Department of Gastrointestinal and Pediatric Surgery, Oslo University Hospital, Ullevål, Norway.

Background: Ingestion of AndoSan™, based on the mushroom Agaricus blazei Murill, has previously been shown to exhibit anti-inflammatory effects because of reduction of pro-inflammatory cytokines in healthy individuals and patients with ulcerative colitis. In this randomized single-blinded placebo controlled study we examined whether intake of AndoSan™ also resulted in clinical effects.

Methods And Findings: 50 patients with symptomatic ulcerative colitis were block-randomized and blinded for oral daily intake of AndoSan™ or placebo for the 21 days' experimental period. The patients reported scores for symptoms, fatigue and health related quality of life (HRQoL) at days 0, 14 and 21. Fecal calprotectin and general blood parameters were also analyzed. In the AndoSan™ group (n = 24) symptoms improved from baseline (day 0) to days 14 and 21, with respective mean scores (95% CI) of 5.88 (4.92-6.83), 4.71 (3.90-5.52) (p = 0.002) and 4.50 (3.70-5.30) (p = 0.001). Corresponding improved mean scores (±SD) for total fatigue were 16.6 (5.59), 14.1 (4.50) (p = 0.001) and 15.1 (4.09) (p = 0.023). These scores in the placebo group (n = 26) were not improved. When comparing the two study groups using mixed model statistics, we found significant better scores for the AndoSan™-patients. HRQoL for dimensions bodily pain, vitality, social functioning and mental health improved in the AndoSan™ group. There were no alterations in general blood samples and fecal calprotectin.

Conclusions: Beneficiary effects on symptoms, fatigue and HRQoL from AndoSan™ consumption were demonstrated in this per-protocol study, supporting its use as a supplement to conventional medication for patients with mild to moderate symptoms from ulcerative colitis. The patients did not report any harms or unintended effects of AndoSan™ in this study.

Trial Registration: ClinicalTrials.gov NCT01496053.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774976PMC
July 2016

Immunomodulatory effects of the Agaricus blazei Murrill-based mushroom extract AndoSan in patients with multiple myeloma undergoing high dose chemotherapy and autologous stem cell transplantation: a randomized, double blinded clinical study.

Biomed Res Int 2015 18;2015:718539. Epub 2015 Jan 18.

Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway ; Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.

Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found. Whole genome microarray showed increased expression of immunoglobulin genes, Killer Immunoglobulin Receptor (KIR) genes, and HLA genes in the Agaricus group. Furthermore, AndoSan displayed a concentration dependent antiproliferative effect on mouse myeloma cells in vitro. There were no statistically significant differences in treatment response, overall survival, and time to new treatment. The study was registered with Clinicaltrials.gov NCT00970021.
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http://dx.doi.org/10.1155/2015/718539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312620PMC
October 2015

The polar high molecular weight fraction of the Agaricus blazei Murill extract, AndoSan™, reduces the activity of the tumor-associated protease, legumain, in RAW 264.7 cells.

J Med Food 2015 Apr 19;18(4):429-38. Epub 2014 Aug 19.

1 Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo , Oslo, Norway .

AndoSan™ is an extract of Agaricus blazei Murill (AbM; 82.4%), Hericium erinaceum (14.7%), and Grifola frondosa (2.9%). The main ingredient of AndoSan, AbM, is rich in different forms of β-glucans. Since these exhibit potent antitumor activity and have immunomodulatory effects, the stimulatory effect of AndoSan on the production of different cytokines, chemokines, and leukocyte growth factors has predominantly been attributed to β-glucans. AndoSan has been claimed to consist of 90% carbohydrate, of which 2.8% is β-glucans, but in this study, we show that the carbohydrate content is only 2% of the dry weight, corresponding to 0.09% β-glucan per mL of AndoSan. Fractionation of AndoSan, followed by carbohydrate analysis and HPLC analysis revealed that most of the glucose was concentrated in the polar high molecular weight fraction of AndoSan (ethanol insoluble water extract [EIWE]-A) and that this extract was able to significantly inhibit the activity of the tumor-associated protease, legumain, in RAW 264.7 cells. Legumain is synthesized as a zymogen and undergoes pH-dependent autoactivation of the proform to reach an enzymatically active form. In this study, we demonstrate that both the polar and nonpolar AndoSan fractions are able to inhibit the autoactivation of prolegumain, and that the polar fractions of AndoSan are the most potent inhibitors of the active form of the enzyme.
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http://dx.doi.org/10.1089/jmf.2014.0018DOI Listing
April 2015

Effect of AndoSan™ on expression of adhesion molecules and production of reactive oxygen species in human monocytes and granulocytes in vivo.

Scand J Gastroenterol 2012 Sep 8;47(8-9):984-92. Epub 2012 May 8.

Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.

Background: Oral intake (60 ml daily) over 12 days in eight healthy volunteers of an immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM (AndoSan™)), reduced the monocyte and granulocyte release of mainly proinflammatory cytokines in vivo, suggesting an anti-inflammatory effect. In this foremost in vivo study, the aim was to examine the effect of such AndoSan™ consumption on the expression of adhesion molecules CD11b, CD11c and CD62L and production of reactive oxygen species (ROS) in leukocytes.

Methodology/principal Findings: As shown by flow cytometry, there was a significant increase of CD62L expression on monocytes and granulocytes from before (day 0) compared with 12 days after daily AndoSan™ consumption. However, only minor alterations and no clear trend in the expression of CD11b and CD11c were detected. Intracellular ROS (mainly superoxide ion) were significantly reduced in these cells from days 0 to 12.

Conclusions/significance: These results support that oral intake of AndoSan™ exhibits an anti-inflammatory effect in humans in vivo.
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http://dx.doi.org/10.3109/00365521.2012.660544DOI Listing
September 2012

The Mushroom Agaricus blazei Murill Elicits Medicinal Effects on Tumor, Infection, Allergy, and Inflammation through Its Modulation of Innate Immunity and Amelioration of Th1/Th2 Imbalance and Inflammation.

Adv Pharmacol Sci 2011 6;2011:157015. Epub 2011 Sep 6.

Department of Cellular Therapy, The Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0130 Oslo, Norway.

The medicinal mushroom Agaricus blazei Murill from the Brazilian rain forest has been used in traditional medicine and as health food for the prevention of a range of diseases, including infection, allergy, and cancer. Other scientists and we have examined whether there is scientific evidence behind such postulations. Agaricus blazei M is rich in the immunomodulating polysaccharides, β-glucans, and has been shown to have antitumor, anti-infection, and antiallergic/-asthmatic properties in mouse models, in addition to anti-inflammatory effects in inflammatory bowel disease patients. These effects are mediated through the mushroom's stimulation of innate immune cells, such as monocytes, NK cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation.
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http://dx.doi.org/10.1155/2011/157015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168293PMC
November 2011

Allergic sensitisation in tuberculosis patients at the time of diagnosis and following chemotherapy.

BMC Infect Dis 2009 Jun 26;9:100. Epub 2009 Jun 26.

Department of Environmental Immunology, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway.

Background: It is still a matter of debate whether there is an association between infection with Mycobacterium tuberculosis (M. tuberculosis) and allergy. Previously, we have shown higher levels of specific IgE to different inhalant allergens and total IgE in tuberculosis (TB) patients compared to controls. The objectives of this study were to evaluate a possible change in allergic sensitisation after successful TB treatment and to confirm the finding of our previous study of enhanced allergic sensitisation in TB patients compared to controls in a more controlled setting. Additionally, we wanted to determine the cytokine profile in the same groups and finally to evaluate the association between the presence of Bacillus Calmette-Guérin vaccination (BCG) scar and allergic sensitisation among the controls.

Methods: Sera were analysed for specific IgE to inhalant allergens (Phadiatop) and total IgE by the use of ImmunoCAP 1000 (Pharmacia Diagnostics). Thirteen different cytokines were also analysed in the sera by multiplex bead immunoassay (Luminex 100, Luminex Corporation), and clinical symptoms of allergy and BCG scar were reported in a questionnaire.

Results: A reduction in levels of specific and total IgE were observed after successful TB treatment. TB patients also had higher levels of specific and total IgE compared to healthy controls. Both interleukin (IL)-6 and interferon (IFN)gamma were higher in TB patients compared to healthy controls. The levels of IL-6 were reduced after successful TB treatment. The presence of a BCG scar was associated with a reduced risk of developing allergic sensitisation.

Conclusion: We observed a reduced level of allergic sensitisation after successful TB treatment. TB patients seem to be more allergically sensitised than healthy controls, confirming our previous finding. Furthermore, we observed an inverse association between allergic sensitisation and visible BCG scar, which adds additional support to the hygiene hypothesis.
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http://dx.doi.org/10.1186/1471-2334-9-100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711955PMC
June 2009

An extract of the medicinal mushroom Agaricus blazei Murill can protect against allergy.

Clin Mol Allergy 2009 May 5;7. Epub 2009 May 5.

Department of Immunology and Transfusion Medicine, Oslo University Hospital, Ulleval, Oslo, Norway.

Background: Agaricus blazei Murill (AbM) is an edible Brazilian mushroom that has been used in traditional medicine for a range of diseases. It has been shown to have anti-infection and anti-tumor properties in the mouse, which are due to induction of Th1 responses. On the other hand, IgE-mediated allergy is induced by a Th2 response.

Objective: Since according to the Th1/Th2 paradigm an increased Th1 response may promote a reduced Th2 response, the aim was to examine whether AbM had anti-allergy effects.

Methods: A mouse model for allergy was employed, in which the mice were immunized s.c. with the model allergen ovalbumin (OVA). Additionally, the animals were given a mushroom extract, AndoSan, mainly (82%) containing AbM, but also Hericium erinaceum (15%) and Grifola frondosa (3%), or PBS p.o. either a day before or 19 days after the immunization. The mice were sacrificed on day 26, and anti-OVA IgE (Th2 response) and IgG2a (Th1 response) antibodies were examined in serum and Th1, Th2 and Treg cytokines in spleen cells cultures.

Results: It was found that the AndoSan extract both when given either before or after OVA immunization reduced the levels of anti-OVA IgE, but not IgG2a, in the mice. There was a tendency to reduced Th2 relative to Th1 cytokine levels in the AndoSan groups.

Conclusion: This particular AbM extract may both prevent allergy development and be used as a therapeutical substance against established allergy.
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http://dx.doi.org/10.1186/1476-7961-7-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688003PMC
May 2009

Effect of an extract of the mushroom Agaricus blazei Murill on expression of adhesion molecules and production of reactive oxygen species in monocytes and granulocytes in human whole blood ex vivo.

APMIS 2007 Jun;115(6):719-25

Department of Gastroenterological Surgery, Ulleval University Hospital, Oslo, Norway.

We have reported that an extract of the edible officinal mushroom Agaricus blazei Murill (AbM) stimulates synthesis of pro-inflammatory cytokines in human monocytes and vein endothelial cells in vitro and reduces the extent of lethal septicemia in mice with bacterial peritonitis. In the present study on human monocytes and granulocytes in whole blood ex vivo, we studied the dynamic changes of cell adhesion molecules (CD11b, CD62L) and the production of reactive oxygen species (ROS) after stimulation with AbM. The presence of AbM resulted in a similarly increased expression of CD11b in monocytes and granulocytes, although at a lower AbM concentration in monocytes (0.5%) than in granulocytes (2%). Furthermore, there was an AbM-mediated decrease in CD62L expression mirroring the effect on CD11b expression regarding magnitude and dose response. The intracellular production of ROS increased slightly but significantly in granulocytes, but not in monocytes stimulated with AbM. The results suggested that the major effect of AbM on monocytes and granulocytes was the upregulation of CD11b expression, thereby increasing both the phagocytic potential and the ablility to induce diapedesis into inflammatory foci. The rich beta-glucan content of AbM could play a crucial role in this immune response.
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http://dx.doi.org/10.1111/j.1600-0463.2007.apm_619.xDOI Listing
June 2007

Quantification and characterisation of IgG binding to mould spores by flow cytometry and scanning electron microscopy.

J Immunol Methods 2007 Jun 27;323(2):123-31. Epub 2007 Apr 27.

Department of Environmental Immunology, Norwegian Institute of Public Health, Oslo, Norway.

The concentration of mould-specific IgG antibodies in serum may objectively indicate mould exposure and can help identifying exposed individuals. Although inhaled spores probably are the most important source of mould exposure, the commonly used methods for detecting mould-specific IgG antibodies are based on extracts from all mould components, with only low contribution from spores. We have developed a flow cytometric method using surface antigens on mould spores for quantifying mould-specific IgG antibodies in serum. Flow cytometric results were evaluated by comparison with ImmunoCap and ELISA measurements. The flow cytometric assay showed a broad linear dose-dependency and correlated moderately to strongly (r=0.41-0.97) with ImmunoCap and ELISA measurements. The IgG antibody binding was studied in detail by immunolabelling in scanning electron microscopy (SEM), revealing that morphology and IgG antibody binding differed among spores, both within and between mould strains. Germination studies by flow cytometry and SEM showed that IgG antibody binding to mould spores was altered during germination due to loss of coat. The present spore based antibody assay are simple and suitable for quantification of mould-specific IgG antibodies in serum, and includes specificity to other and possibly more relevant antigens than existing methods.
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http://dx.doi.org/10.1016/j.jim.2007.04.001DOI Listing
June 2007

An extract of the medicinal mushroom Agaricus blazei Murill differentially stimulates production of pro-inflammatory cytokines in human monocytes and human vein endothelial cells in vitro.

Inflammation 2005 Dec;29(4-6):147-53

Department of Gastroenterological Surgery, Ulleval University Hospital, Kirkeveien 166, 0407 Oslo, Norway.

An extract of the edible mushroom Agaricus blazei Murill (AbM) has known antitumor and anti-infection properties, probably mainly by stimulating mononuclear phagocytes of the native immune system. The aim of this work was to study the effect of AbM on the production by human monocytes and human umbilical vein endothelial cells (EC) of pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, TNFalpha), the anti-inflammatory/T regulatory cytokine IL-10 and the pro-Th1 cytokine IL-12. AbM, in concentrations from 1-15%, induced a considerable and dose-dependent increase in production of IL-8, IL-6, TNFalpha and IL-1beta in monocyte cultures. The biosynthesis reached a plateau at a concentration of 10% of AbM, and was most pronounced for the three former cytokines. AbM did also dose-dependently stimulate EC production of IL-8,I L-6 and TNFalpha, but at lower levels compared with the monocytes. AbM did neither induce synthesis of cytokines IL-10 nor IL-12 in monocytes or EC. Our results demonstrate the differential effect of AbM stimulation on the magnitude of pro-inflammatory cytokines produced by monocytes and EC.
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http://dx.doi.org/10.1007/s10753-006-9010-2DOI Listing
December 2005

An extract of the mushroom Agaricus blazei Murill protects against lethal septicemia in a mouse model of fecal peritonitis.

Shock 2006 Apr;25(4):420-5

Department of Gastroenterological Surgery, Ulleval University Hospital, Oslo, Norway.

Bacterial septicemia is frequently occurring during gastroenterological surgery. Because of increasing problems in hospitals with bacteria developing multiresistance against antibiotics, prophylactic treatment using immunomodulators is interesting. We have examined the putatively anti-infective immunomodulatory action of the edible mushroom, Agaricus blazei Murill (AbM), in an experimental peritonitis model in BALB/c mice. The mice were orally given an extract of AbM or phosphate-buffered saline 1 day before the induction of peritonitis with various concentrations of feces from the mice. The state of septicemia, as measured by the number of colony-forming units of bacteria in blood, and the survival rate of the animals were compared between the groups. Mice that were orally treated with AbM extract before bacterial challenge showed significantly lower levels of septicemia and improved survival rates. Our findings suggest that the AbM extract, when given prophylactically, may improve health. Further studies are needed on humans when considering whether AbM could be used as an alternative treatment modality for patients at risk of contracting serious bacterial peritonitis.
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http://dx.doi.org/10.1097/01.shk.0000209526.58614.92DOI Listing
April 2006

The fungal biopesticide Metarhizium anisopliae has an adjuvant effect on the allergic response to ovalbumin in mice.

Toxicol Lett 2006 Mar 10;161(3):219-25. Epub 2005 Oct 10.

Norwegian Institute of Public Health, Division of Environmental Medicine, P.O. Box 4404 Nydalen, Oslo 0403, Norway.

The parasitic fungus, Metarhizium anisopliae, is non-pathogenic to humans and licensed for indoor control of cockroach infestation. An important reason for the elimination of this vermin is that sensitisation to cockroaches is associated with asthma. Previously M. anisopliae has been shown to cause allergic- and asthma-like responses in mice and in the present study we have examined the adjuvant activity of M. anisopliae on the allergic response to the model allergen ovalbumin (OVA) in a mouse model. Levels of OVA-specific IgE, IgG1 and IgG2a in serum were measured and the weight and cell number of the excised popliteal lymph node were determined. Mice primed with mycelium+OVA and boosted with OVA had increased anti-OVA IgE and IgG1 levels compared with mice primed with OVA alone or mycelium. Priming with M. anisopliae (as mycelium or MACA) increased weight or cell number of the excised PLNs. These results suggest that M. anisopliae has the ability to increase an allergic response to an allergen and consequently, may worsen allergy in susceptible individuals.
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http://dx.doi.org/10.1016/j.toxlet.2005.09.006DOI Listing
March 2006

Deoxynivalenol (DON) is toxic to human colonic, lung and monocytic cell lines, but does not increase the IgE response in a mouse model for allergy.

Toxicology 2004 Nov;204(1):13-21

Department of Environmental Immunology, Division of Environmental Medicine, Norwegian Institute of Public Health, Geitmyrsv. 75, 0462 Oslo, Norway.

We examined whether the common crop mycotoxin deoxynivalenol (DON) from Fusarium species is toxic to human colonic (Caco-2), lung (A549) and monocytic (U937) cell lines. Moreover, since DON reportedly induces increased levels of Th2 cytokines and total IgE, and we have observed that mould extracts adjuvated allergy development in mice, possible adjuvant effect of DON on allergy was studied in a mouse model. For all the cells, exposure to DON for 24 h reduced cellular protein synthesis, proliferation and survival rate dose-dependently. In addition, production of IL-8 in the U937 cell line increased up to eight-fold at levels of DON just lower than the most toxic one, suggesting that IL-8 can be used as an additional index for cytotoxicity in mononuclear phagocytes. However, DON did not increase levels of allergen-specific IgE or IgG1 in the mouse model for allergy. These results suggest that DON, when inhaled or ingested, may have toxic effect on human alveolar macrophages and epithelial cells in lungs and colon, but does not increase the allergic response to allergens.
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http://dx.doi.org/10.1016/j.tox.2004.05.011DOI Listing
November 2004

HUVEC take up opsonized zymosan particles and secrete cytokines IL-6 and IL-8 in vitro.

FEMS Immunol Med Microbiol 2003 May;36(1-2):55-61

Research Forum and Department of Pediatrics, Ullevål University Hospital, Kirkevej Kirkeveien 166, 0404 Oslo, Norway.

Uptake of zymosan A particles by human umbilical vein endothelial cells (HUVEC) and its effect on cellular cytokine and oxygen radical production was examined. HUVEC took up more serum-opsonized than -unopsonized zymosan as demonstrated by flow cytometry with fluorescence-labeled particles. The former uptake was inhibited in the presence of anti-C3c antibodies and thus complement-mediated. It probably occurred via CR1 (CD35), although participation of other receptors cannot be ruled out. Scanning electron microscopy indicated that HUVEC with fully internalized zymosan particles were damaged. Prolonged incubation of both serum-opsonized and -unopsonized zymosan particles with HUVEC induced increased secretion of the proinflammatory cytokines IL-6 and IL-8 to the cell culture supernatants, but had no effect on production of oxygen radicals. The results confirm previous reports that EC can internalize yeast and other pathogens and points to complement as a mechanism of uptake, but illustrates that the cells may be damaged in the process. Moreover, EC may participate in the anti-infection defense effort by secreting proinflammatory and chemotactic cytokines in response to the contact with pathogens.
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http://dx.doi.org/10.1016/S0928-8244(03)00033-6DOI Listing
May 2003

Human umbilical vein endothelial cells express complement receptor 1 (CD35) and complement receptor 4 (CD11c/CD18) in vitro.

Inflammation 2002 Jun;26(3):103-10

Research Forum, Ullevål Hospital, University of Oslo, Norway.

We have examined complement receptors on human umbilical vein endothelial cells (HUVEC) and found that they express complement receptor 1 (CR1, CD35) and complement receptor 4 (CR4, CD11c/CD18), but not complement receptor 3 (CR3, CD11b/CD18). Binding of monoclonal antibodies against CR1 (CD35) and CR4 (CD11c/CD18) to HUVEC was demonstrated by flow cytometry. The presence of the corresponding mRNAs was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing of the amplified cDNA fragments. When HUVEC were treated with inflammatory mediators, chemotactic agents or the secretagogue phorbol-12-myristate-13-acetate (PMA), no change in reactivity to CR1 (CD35) or CR4 (CD11c/CD18) monoclonal antibodies was detected on the surface of the cells compared with untreated cells. The presence of CR1 (CD35) and CR4 (CD1c/CD18) on HUVEC indicates that endothelial cells (EC) have the potential to bind C3b and iC3b, respectively, which both mediate biological effects in the course of complement activation.
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http://dx.doi.org/10.1023/a:1015585530204DOI Listing
June 2002

beta-1,3-Glucan reduces growth of Mycobacterium tuberculosis in macrophage cultures.

FEMS Immunol Med Microbiol 2002 Mar;33(1):41-5

Department of Environmental Medicine, National Institute of Public Health, P.O. Box 4404 Nydalen, 0403 Oslo, Norway.

The effect of beta-1,3-D-glucans SSG, from Sclerotinia sclerotiorum, or soluble (sMG) or particulate (pMG) MacroGard from baker's yeast on growth of Mycobacterium tuberculosis H37Rv in cultures of peritoneal macrophages from BALB/c mice was examined. After 24 h intracellular bacteria from lysed macrophages were cultured and the number of cfu counted. SSG given with challenge, but not 24 h after, reduced the number of M. tuberculosis cfu significantly. pMG, but not sMG, given with challenge had an even stronger inhibitory effect, which was enhanced after serum opsonization of the particles. The effect of serum-treated pMG was abrogated by addition of a monoclonal antibody to CD11b. The results indicate that beta-glucans inhibit growth of M. tuberculosis in host cells in vitro, probably due to cellular stimulation and/or competitive inhibition of uptake of bacteria via CR3 (CD11b/18).
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http://dx.doi.org/10.1111/j.1574-695X.2002.tb00570.xDOI Listing
March 2002
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