Publications (6)30.9 Total impact
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Article: Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation.
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ABSTRACT: Asthma is a respiratory tract disorder characterized by airway hyper-reactivity and chronic inflammation. Allergic asthma is associated with the production of allergen-specific IgE and expansion of allergen-specific T-cell populations. Progression of allergic inflammation is driven by T-helper type 2 (Th2) mediators and is associated with alterations in the levels of lipid mediators. Responses of the respiratory system to birch allergen provocation in allergic asthmatics were investigated. Eicosanoids and other oxylipins were quantified in the bronchoalveolar lumen to provide a measure of shifts in lipid mediators associated with allergen challenge in allergic asthmatics. Eighty-seven lipid mediators representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS following off-line extraction of bronchoalveolar lavage fluid (BALF). Multivariate statistics using OPLS were employed to interrogate acquired oxylipin data in combination with immunological markers. Thirty-two oxylipins were quantified, with baseline asthmatics possessing a different oxylipin profile relative to healthy individuals that became more distinct following allergen provocation. The most prominent differences included 15-LOX-derived ω-3 and ω-6 oxylipins. Shared-and-Unique-Structures (SUS)-plot modeling showed a correlation (R(2) = 0.7) between OPLS models for baseline asthmatics (R(2)Y[cum] = 0.87, Q(2)[cum] = 0.51) and allergen-provoked asthmatics (R(2)Y[cum] = 0.95, Q(2)[cum] = 0.73), with the majority of quantified lipid mediators and cytokines contributing equally to both groups. Unique structures for allergen provocation included leukotrienes (LTB(4) and 6-trans-LTB(4)), CYP-derivatives of linoleic acid (epoxides/diols), and IL-10. Differences in asthmatic relative to healthy profiles suggest a role for 15-LOX products of both ω-6 and ω-3 origin in allergic inflammation. Prominent differences at baseline levels indicate that non-symptomatic asthmatics are subject to an underlying inflammatory condition not observed with other traditional mediators. Results suggest that oxylipin profiling may provide a sensitive means of characterizing low-level inflammation and that even individuals with mild disease display distinct phenotypic profiles, which may have clinical ramifications for disease.PLoS ONE 01/2012; 7(3):e33780. · 4.09 Impact Factor -
Article: Mesenchymal stem cells inhibit thymic reconstitution after allogeneic cord blood transplantation.
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ABSTRACT: Cord blood (CB) as a source of stem cells has been a successful addition to the field of allogeneic stem cell transplantation (ASCT). The increased human leukocyte antigen (HLA) permissiveness of CB grafts has made it possible for more patients to undergo treatment. The drawback is that patients suffer from a longer period of compromised immunity. We analyzed T-cell receptor excision circles (TRECs), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels after cord blood transplantation (CBT) in 50 patients transplanted at our center. These immunological parameters were compared retrospectively with clinical factors and complications. We found that TREC levels after CBT were lower in adults, patients with myeloablative conditioning, and in patients with a lower nucleated cell dose in the graft. In addition mesenchymal stem cells (MSC) as co-infusion at the time of CBT had a negative effect on TREC reconstitution. This was found to be associated with decreased overall survival for this patient category. Reduced IgM and IgG levels post-CBT were associated with a major AB0 mismatch, and infusion of MSCs. Our results highlight the importance of close monitoring of the immune reconstitution after CBT. In addition it shows a potentially new suppressive effect of MSCs on the immune system.Stem cells and development 08/2011; 21(9):1409-17. · 4.15 Impact Factor -
Article: Low levels of endotoxin enhance allergen-stimulated proliferation and reduce the threshold for activation in human peripheral blood cells.
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ABSTRACT: Endotoxins, comprised of bacterial cell wall lipopolysaccharides (LPS), have been reported to have both protective and exacerbating effects on the development and maintenance of allergic disease in humans and on markers of allergic inflammation in animal models of allergy. In this study, we investigated the effect of low concentrations of LPS on human peripheral blood mononuclear cells (PBMC) stimulated with the major cat allergen Fel d 1. Extensive purification of recombinant (r) Fel d 1 yielded essentially endotoxin-free rFel d 1 (0.2 ng LPS /mg protein). PBMCs prepared from 15 subjects having IgE to cat (>0.7 kU(A)/l) and 8 subjects IgE negative to cat were stimulated with 2, 10 or 25 microg/ml of rFel d 1 in the presence or absence of 50 pg/ml LPS. Proliferation was measured after 7 days of culture and supernatants were analyzed for IFNgamma, IL-5 and IL-10. LPS (50 pg/ml) increased rFel d 1-stimulated proliferation of PBMCs both from subjects IgE-positive and subjects negative to cat allergens. PBMCs from 13 of the subjects did not proliferate in response to stimulation with 2 and 10 microg/ml rFel d 1 alone but did so in the presence of LPS. Moreover, LPS increased the levels of rFel d 1-stimulated IFNgamma in cultures from cat-negative subjects, IL-5 from cat-positive subjects and IL-10 from both groups. Very low doses of LPS enhance proliferation and decrease the apparent threshold level for cell activation, prompting careful evaluation of allergen stimulated T cell activation in vitro.International Archives of Allergy and Immunology 01/2008; 146(1):1-10. · 2.40 Impact Factor -
Article: Structural characterization of the tetrameric form of the major cat allergen Fel d 1.
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ABSTRACT: Felis domesticus allergen 1(Fel d 1) is a 35 kDa tetrameric glycoprotein formed by two heterodimers which elicits IgE responses in 95% of patients with allergy to cat. We have previously established in vitro conditions for the appropriate folding of recombinant Fel d 1 using a direct linkage of chain 1 to chain 2 (construct Fel d 1 (1+2)) and chain 2 to chain 1 (construct Fel d 1 (2+1)). Although the crystal structure of Fel d 1 (2+1) revealed a striking structural similarity to that of uteroglobin, a steroid-inducible cytokine-like molecule with anti-inflammatory and immunomodulatory properties, no functional tetrameric form of Fel d 1 could be identified. Here we present the crystal structure of the Fel d 1 (1+2) tetramer at 1.6 A resolution. Interestingly, the crystal structure of tetrameric Fel d 1 reveals two different calcium-binding sites. Symmetrically positioned on each side of the Fel d 1 tetramer, the external Ca(2+)-binding sites correspond to a putative Ca(2+)-binding site previously suggested for uteroglobin. The second Ca(2+)-binding site lies within the dimerization interface, stabilizing the formation of the Fel d 1 tetramer, and inducing important local conformational changes that directly govern the shape of two water-filled cavities. The crystal structure suggests a potential portal for an unknown ligand. Alternatively, the two cavities could be used by the allergen as a conditional inner space allowing for the spatial rearrangement of centrally localized side-chains, such as Asp130, without altering the overall fold of the molecule. The striking structural similarity of the major cat allergen to uteroglobin, coupled to the identification in the present study of a common Ca(2+)-binding site, let us speculate that Fel d 1 could provoke an allergic response through the modulation of phospholipase A2, by sequestering Ca ions in a similar manner as previously suggested for uteroglobin.Journal of Molecular Biology 08/2007; 370(4):714-27. · 4.00 Impact Factor -
Article: Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1.
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ABSTRACT: Recently, recombinant hypoallergenic derivatives of the major birch pollen allergen, Bet v 1, were used to treat birch-pollen-allergic patients in a double-blind, placebo-controlled, multi-centre immunotherapy study. The aim of this study was to evaluate the effects of vaccination with aluminium-hydroxide-adsorbed recombinant Bet v 1 derivatives versus placebo on T-cell, cytokine and antibody responses in a subgroup of patients. Blood was drawn from patients of the Swedish centre (n = 27; rBet v 1 fragments: n = 10; rBet v 1 trimer: n = 8, and placebo-aluminium hydroxide: n = 9) before the start and after completion of the treatment. PBMC were stimulated with rBet v 1 and analysed for cytokine (IL-4, IL-5, IL-10, IL-12, IL-13 and IFN-gamma)-secreting cells by ELISpot. Bet v 1-specific antibody levels in serum (IgG(1-4), IgE and IgA) were measured by ELISA. Skin prick tests with defined Bet v 1 concentrations were performed before and 10-11 months after the beginning of the study. Bet v 1-specific IgG levels, consisting of IgG(1), IgG(2) and IgG(4), were significantly increased after treatment with recombinant allergen derivatives. Treatment with rBet v 1 trimer led to a significant (p < 0.05) reduction of Bet v 1-reactive IL-5- and IL-13-producing cells, reflecting a reduced Th2 response. In addition, a decreased number of Bet v 1-reactive IL-4 producing (p = 0.07) and an increase of IL-12-producing (p = 0.06) cells was noted in the trimer-treated patients. In contrast to placebo, active treatment resulted in significantly reduced immediate-type skin reactions to Bet v 1 even 10-11 months after treatment. Vaccination with recombinant hypoallergenic Bet v 1 derivatives induces a Bet v 1-specific IgG response and leads to reduced skin reactivity in allergic patients. A reduction of Bet v 1-specific Th2 responses was observed in trimer-treated patients, which may reflect the intrinsic property of this allergen derivative.International Archives of Allergy and Immunology 10/2005; 138(1):59-66. · 2.40 Impact Factor -
Article: Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.
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ABSTRACT: The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-gamma-, interleukin (IL)-4-, and IL-10-producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.Journal of Experimental Medicine 07/2004; 199(11):1567-75. · 13.85 Impact Factor
