| 1. |
- Johansson, Anna-Karin, 1974, et al.
(författare)
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Allergen stimulates bone marrow CD34
- 2004
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Ingår i: Allergy. ; 59:10
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Tidskriftsartikel (refereegranskat)abstract
- The specific mechanisms that alter bone marrow (BM) eosinophilopoiesis in allergen-induced inflammation are poorly understood. The aims of this study were to evaluate (a) whether the number of BM CD34(+) cells is altered due to allergen sensitization and exposure in vivo and (b) whether BM CD34(+) cells produce and release interleukin (IL)-5, IL-3 and granulocyte macrophage-colony stimulating factor (GM-CSF) after stimulation in vitro. A mouse model of ovalbumin (OVA)-induced airway inflammation was used. Bone marrow CD34(+) cells were cultured in vitro and the cytokine release was measured by enzyme-linked immunosorbent assay. The IL-5-production from CD34(+) cells was confirmed by immunocytochemistry. Airway allergen exposure increased the number of BM CD34(+) cells (P = 0.01). Bone marrow CD34(+) cells produced IL-5 when stimulated with the allergen OVA in vitro, but not IL-3 or GM-CSF. Nonspecific stimulus with calcium ionophore and phorbol-myristate-acetate of BM CD34(+) cells caused release of IL-5, IL-3 and GM-CSF. The induced release of IL-5 was increased in alum-injected vs naive mice (P = 0.02), but was not affected by allergen sensitization and exposure. The release of IL-3 and GM-CSF was increased after allergen sensitization and exposure (P < 0.02). In conclusion, allergen can stimulate BM CD34(+) cells to produce IL-5 protein. It is likely that the CD34(+) cells have autocrine functions and thereby regulate the early stages of BM eosinophilopoiesis induced by airway allergen exposure. Alum, a commonly used adjuvant, enhances the release of IL-5 and may thereby enhance eosinophilopoiesis.
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| 2. |
- Sergejeva, Svetlana, 1972, et al.
(författare)
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Intranasal fluticasone propionate inhibits allergen induced bone marrow eosinophilia in mice.
- 2002
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Ingår i: Pulmonary pharmacology & therapeutics. - : Elsevier BV. - 1094-5539. ; 15:2, s. 129-34
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Tidskriftsartikel (refereegranskat)abstract
- Local corticosteroids are currently the most efficient safe anti-allergic treatment, which attenuate eosinophilic tissue inflammation through several mechanisms. We evaluated the effect of local airways corticosteroid on repeated allergen exposure-induced bone marrow activation and airway eosinophilia using the number of eosinophils in bone marrow, bronchoalveolar lavage fluid (BALf) and airways tissue as study end-points. Male BALB/c mice were sensitized by intraperitoneal injections of aluminum-precipitated ovalbumin (OVA) on two different days (5 days apart). Eight days after the second sensitization, the animals were challenged intranasally with OVA or phosphate-buffered saline (PBS) on 5 consecutive days. Concomitantly with challenges mice were treated with fluticasone propionate or respective vehicle. OVA exposures induced a significant increase in eosinophil numbers in bone marrow, BALf and airways tissue (P<0.005). Treatment with fluticasone propionate significantly reduced the increase of absolute number of mature bone marrow eosinophils (P=0.014) and showed a tendency towards decrease in the immature bone marrow eosinophil number (P=0.057) compared to controls. However, fluticasone propionate had no significant effect on BALf and airways tissue eosinophils (P=0.28 and 0.07, respectively). In this murine allergy model intranasal corticosteroid reduced number of bone marrow mature eosinophils, but did not significantly affect airways cell populations.
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| 3. |
- Tomaki, Masafumi, 1964
(författare)
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Airway allergic inflammation. A role of bone marrow and relationship to substance P
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Airway inflammation, along with reversible airway narrowing and airway hyperresponsiveness, is a central pathophysiological feature of bronchial asthma. The airway inflammation in asthma is dominated by eosinophils, cells that originate in the bone marrow. However, the precise mechanisms of the interaction between the airways and the bone marrow in the inflammatory process are less well known.The aim of this thesis was to determine the contribution of newly produced eosinophils to airway allergic inflammation, and the mechanisms of enhanced eosinophilopoiesis induced by allergen exposure. Furthermore the relationship between eosinophilic airway inflammation and substance P was investigated.Ovalbumin-sensitised Balb/c mice were repeatedly exposed to allergen via the airway route. Newly produced cells were identified using the thymidine analogue bromodeoxyuridine (BrdU), which is incorporated into DNA during cell mitosis. Anti-IL-3, anti-IL-5 and anti-GM-CSF treatments were given either systemically or directly to the airways. Identification of IL-5-producing cells in the bone marrow was performed using FACS. Bone marrow CD3+ cells were enriched to evaluate IL-5 protein release in vitro. IL-5-receptor bearing cells were localised by immunocytochemistry. In the human studies, eosinophilic inflammation was evaluated in induced sputum from patients with asthma. Substance P (SP) concentration in induced sputum was measured by radioimmunoassay.Repeated airway allergen exposure caused prominent airway eosinophilia after 3-5 exposures, and increased the number of immature eosinophils in the bone marrow. Up to 78% of BAL granulocytes were BrdU-positive. Anti-IL-5 given intraperitoneally inhibited both bone marrow and airway eosinophilia. Intranasal administration of anti-IL-5 also reduced BAL eosinophilia, to some degree via inhibition of bone marrow eosinophilia. The combined inhibition of IL-3 and GM-CSF reduced bone marrow and airway eosinophilia. After three allergen exposures, CD3+ cells acquired from the bone marrow expressed and released IL-5 protein. Bone marrow cells, but not BAL eosinophils, displayed stainable amounts of the IL-5-receptor a-chain. The sputum SP concentration in patients with asthma was significantly higher than in healthy volunteers, and inversely related to the degree of airway narrowing. In asthmatic subjects, the sputum eosinophil content correlated with the SP concentration in induced sputum.In conclusion, these data suggest that the bone marrow is activated by airway allergen exposure, and that newly produced eosinophils contribute to a substantial degree to the induced airway eosinophilia. In asthmatic airways, eosinophils may contribute to airway inflammation partly in parallel to SP-mediated inflammatory mechanisms. IL-5 plays a crucial role for the bone marrow activation and the induction of airway eosinophilia. Anti-IL-5-treatment targeted to the bone marrow may be a useful therapeutic approach to inhibit eosinophilic inflammation in asthma.
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| 4. |
- Tomaki, Masafumi, 1964, et al.
(författare)
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Comparison of effects of anti-IL-3, IL-5 and GM-CSF treatments on eosinophilopoiesis and airway eosinophilia induced by allergen
- 2002
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Ingår i: Pulmonary pharmacology & therapeutics. - 1094-5539. ; 15:2, s. 161-8
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Tidskriftsartikel (refereegranskat)abstract
- Allergic inflammation is dominated by eosinophils. IL-3, IL-5, and GM-CSF are involved in production and activation of eosinophils. IL-5 has been reported to be crucial for the induction of airway eosinophilia. However, the contribution of IL-3 and GM-CSF to allergic airway inflammation remains to be determined. To address this issue, ovalbumin-sensitized Balb/c mice were repeatedly exposed to allergen via airway route. Animals were pretreated intraperitoneally with neutralising anti-IL-3, anti-IL-5 and/or anti-GM-CSF antibodies. Newly produced inflammatory cells were pulse-labelled with the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), which is incorporated into DNA during the cell mitosis. BAL and bone marrow cells were collected 24 h after the last allergen exposure, and differential cell counts and immunocytochemical detection of BrdU-labelled cells were performed. Anti-IL-5 strongly reduced both BAL and bone marrow eosinophilia, as well as the number of BrdU-positive BAL-granulocytes. In contrast, anti-IL-3 and anti-GM-CSF alone had little and no inhibitory effect on these responses, respectively. Even the combined treatment with anti-IL-3 and anti-GM-CSF showed only a non-significant tendency to attenuate these responses. These data suggest that the efficacy of treatments with anti-IL-3 and anti-GM-CSF is much weaker than that with anti-IL-5. IL-5 may be the preferred target to block eosinophilia in allergic diseases.
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| 5. |
- Tomaki, Masafumi, 1964, et al.
(författare)
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Eosinophilopoiesis in a murine model of allergic airway eosinophilia: involvement of bone marrow IL-5 and IL-5 receptor alpha
- 2000
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Ingår i: Journal of immunology (Baltimore, Md.. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 165:7, s. 4040-50
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Tidskriftsartikel (refereegranskat)abstract
- The airway inflammation in asthma is dominated by eosinophils. The aim of this study was to elucidate the contribution of newly produced eosinophils in airway allergic inflammation and to determine mechanisms of any enhanced eosinophilopoiesis. OVA-sensitized BALB/c mice were repeatedly exposed to allergen via airway route. Newly produced cells were identified using a thymidine analog, 5-bromo-2'-deoxyuridine, which is incorporated into DNA during mitosis. Identification of IL-5-producing cells in the bone marrow was performed using FACS. Bone marrow CD3+ cells were enriched to evaluate IL-5-protein release in vitro. Anti-IL-5-treatment (TRFK-5) was given either systemically or directly to the airways. IL-5R-bearing cells were localized by immunocytochemistry. Repeated airway allergen exposure caused prominent airway eosinophilia after three to five exposures, and increased the number of immature eosinophils in the bone marrow. Up to 78% of bronchoalveolar lavage (BAL) granulocytes were 5-bromo-2'-deoxyuridine positive. After three allergen exposures, both CD3+ and non-CD3 cells acquired from the bone marrow expressed and released IL-5-protein. Anti-IL-5 given i.p. inhibited both bone marrow and airway eosinophilia. Intranasal administration of anti-IL-5 also reduced BAL eosinophilia, partly via local effects in the airways. Bone marrow cells, but not BAL eosinophils, displayed stainable amounts of the IL-5R alpha-chain. We conclude that the bone marrow is activated by airway allergen exposure, and that newly produced eosinophils contribute to a substantial degree to the airway eosinophilia induced by allergen. Airway allergen exposure increases the number of cells expressing IL-5-protein in the bone marrow. The bone marrow, as well as the lung, are possible targets for anti-IL-5-treatment.
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| 6. |
- Zhao, Lin-Ling, 1957, et al.
(författare)
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Prolonged eosinophil production after allergen exposure in IFN-gammaR KO mice is IL-5 dependent.
- 2008
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 67:5, s. 480-8
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Tidskriftsartikel (refereegranskat)abstract
- Asthma is a T helper 2 (Th2)-driven inflammatory process characterized by eosinophilia. Prolonged airway eosinophilia is commonly observed in asthma exacerbations. Our aim was to evaluate whether eosinophilia in prolonged allergic inflammation is associated with a continuous supply of new eosinophils to the airways, and how this is regulated. Ovalbumin (OVA)-sensitized interferon-gamma receptor knockout mice (IFN-gammaR KO), known to maintain a long-lasting eosinophilia after allergen exposure, were compared to wild type (wt) controls. Animals were exposed to OVA or phosphate-buffered saline on three consecutive days, and bone marrow (BM), blood and bronchoalveolar lavage (BAL) samples were collected 24 h, 7 and 21 days later. Newly produced cells were labelled using bromodeoxyuridine (BrdU). Serum IL-5 was measured and its role was investigated by administration of a neutralizing anti-IL-5 antibody. In-vitro eosinophilopoiesis was examined in both groups by a colony-forming assay. Allergen challenge increased eosinophils in BM, blood and BAL, in both IFN-gammaR KO and wt mice, both 24 h and 7 days after the last allergen exposure. At 21 days after the last exposure, only IFN-gammaR KO mice maintained significantly increased eosinophil numbers. Approximately 50% of BAL granulocytes in IFN-gammaR KO were produced during the last 6 days. Interleukin (IL)-5 concentration was increased in IFN-gammaR KO mice, and anti-IL-5 reduced eosinophil numbers in all compartments. Increased numbers of eosinophil colonies were observed in IFN-gammaR KO mice after allergen exposure versus controls. In this model of a Th2-driven prolonged allergic eosinophilia, new eosinophils contribute to the extended inflammation in the airways by enhanced BM eosinophilopoiesis in an IL-5-dependent manner.
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