| 1. |
- Dao Nyesiga, Gillian, et al.
(författare)
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Tolerogenic dendritic cells generated in vitro using a novel protocol mimicking mucosal tolerance mechanisms represent a potential therapeutic cell platform for induction of immune tolerance.
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) are mediators between innate and adaptive immunity and vital in initiating and modulating antigen-specific immune responses. The most important site for induction of tolerance is the gut mucosa, where TGF-β, retinoic acid, and aryl hydrocarbon receptors collaborate in DCs to induce a tolerogenic phenotype. To mimic this, a novel combination of compounds – the synthetic aryl hydrocarbon receptor (AhR) agonist IGN-512 together with TGF-β and retinoic acid – was developed to create a platform technology for induction of tolerogenic DCs intended for treatment of several conditions caused by unwanted immune activation. These in vitro-generated cells, designated ItolDCs, are phenotypically characterized by their low expression of co-stimulatory and activating molecules along with high expression of tolerance-associated markers such as ILT3, CD103, and LAP, and a weak pro-inflammatory cytokine profile. When co-cultured with T cells and/or B cells, ItolDC-cultures contain higher frequencies of CD25+Foxp3+ regulatory T cells (Tregs), CD49b+LAG3+ ‘type 1 regulatory (Tr1) T cells, and IL-10-producing B cells and are less T cell stimulatory compared to cultures with matured DCs. Factor VIII (FVIII) and tetanus toxoid (TT) were used as model antigens to study ItolDC antigen-loading. ItolDCs can take up FVIII, process, and present FVIII peptides on HLA-DR. By loading both ItolDCs and mDCs with TT, antigen-specific T cell proliferation was observed. Cryo-preserved ItolDCs showed a stable tolerogenic phenotype that was maintained after stimulation with LPS, CD40L, or a pro-inflammatory cocktail. Moreover, exposure to other immune cells did not negatively impact ItolDCs’ expression of tolerogenic markers. In summary, a novel protocol was developed supporting the generation of a stable population of human DCs in vitro that exhibited a tolerogenic phenotype with an ability to increase proportions of induced regulatory T and B cells in mixed cultures. This protocol has the potential to constitute the base of a tolDC platform for inducing antigen-specific tolerance in disorders caused by undesired antigen-specific immune cell activation.
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| 2. |
- Hylander, Terese, et al.
(författare)
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Intralymphatic allergen-specific immunotherapy: An effective and safe alternative treatment route for pollen-induced allergic rhinitis
- 2013
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 131:2, s. 412-420
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergen-specific immunotherapy is the only causative treatment of IgE-mediated allergic disorders. The most common administration route is subcutaneous, which may necessitate more than 50 allergen injections during 3 to 5 years. Recent evidence suggests that direct intralymphatic injections could yield faster beneficial results with considerably lower allergen doses and markedly reduced numbers of injections. Objective: To evaluate the effects of intralymphatic allergen-specific immunotherapy in pollen-allergic patients. Methods: In an open pilot investigation followed by a double-blind, placebo-controlled study, patients with allergic rhinitis were treated with 3 intralymphatic inguinal injections of ALK Alutard (containing 1000 SQ-U birch pollen or grass pollen) or placebo (ALK diluent). Clinical pre- and posttreatment parameters were assessed, the inflammatory cell content in nasal lavage fluids estimated, and the activation pattern of peripheral T cells described. Results: All patients tolerated the intralymphatic immunotherapy (ILIT) treatment well, and the injections did not elicit any severe adverse event. Patients receiving active treatment displayed an initial increase in allergen-specific IgE level and peripheral T-cell activation. A clinical improvement in nasal allergic symptoms upon challenge was recorded along with a decreased inflammatory response in the nose. In addition, these patients reported an improvement in their seasonal allergic disease. No such changes were seen in the placebo group. Conclusions: Although this study is based on a limited number of patients, ILIT with grass-pollen or birch-pollen extracts appears to reduce nasal allergic symptoms without causing any safety problems. Hence, ILIT might constitute a less time-consuming and more cost-effective alternative to conventional subcutaneous allergen-specific immunotherapy. (J Allergy Clin Immunol 2013;131:412-20.)
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| 3. |
- Hylander, Terese, et al.
(författare)
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Intralymphatic immunotherapy of pollen-induced rhinoconjunctivitis: a double-blind placebo-controlled trial.
- 2016
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Allergen-specific immunotherapy represents the only disease-modifying treatment for allergic diseases. We and others have previously demonstrated that intralymphatic immunotherapy (ILIT), a less time-consuming alternative to conventional subcutaneous immunotherapy (SCIT), is safe and effective. However, this has recently been disputed. The aim of this study was therefore to expand our previous trial, further assessing the safety and efficacy of ILIT.
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| 4. |
- Hylander, Terese
(författare)
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Novel potential targets for treatment of airway inflammation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergy is a complex biological response mediated by several different cell types including B lymphocytes, T lymphocytes and eosinophils. From clinical observations it is well-known that microbial infections, in particular viruses, can cause exacerbation of allergic rhinitis and asthma. The underlying mechanisms are still far from understood but recent data indicate that an activation of the immune system via pattern-recognition receptors (PRRs) including NOD-like receptors (NLRs), RIG- like receptors (RLRs) and Toll-like receptors (TLRs) might play a role. These receptors recognize invading microorganisms and enable them to interact directly with an ongoing inflammatory response. In addition, the receptors have been linked to atopic disorders such as allergic rhinitis. Today, allergen-specific immunotherapy is the only treatment that in addition to relieving symptoms also changes the progress of the underlying allergic airway disease. This therapy is traditionally administered through subcutaneous injections during three to four years but recently, intralymphatic allergen-specific immunotherapy (ILIT) emerged as an effective and less time-consuming alternative. The aim of this thesis is to investigate novel targets of potential use for treatment of airway inflammation with special focus on PRRs and ILIT. The first part of the thesis (PAPERS I-III) is focused on NLRs and RLRs in human leukocytes. A range of NLRs and RLRs were detected at mRNA and protein levels. Their expression in B lymphocytes was generally higher in cells derived from peripheral blood than in cells from tonsils. In T cells, a differentiated expression was seen among CD4+ and CD8+ tonsillar cells. Stimulation with cognate ligands in combination with triggering of the B cell receptor (via IgM or IgD) or the T cell receptor (CD3/CD28) promoted lymphocyte activation as shown by enhanced proliferation, up-regulated expression of cell-surface markers, prolonged survival and secretion of cytokines. Concomitant stimulation via the NLR and TLR systems synergistically enhanced the proliferative responses of B cells. Altogether this indicates that lymphocytes have the ability to recognize pathogens via the PRR system and it supports the idea of a role for innate receptors also in the adaptive branch of the immune system. Eosinophils expressed both NLRs and RLRs and stimulation with the NOD1 and NOD2 ligands promoted activation as manifested by the release of cytokines, enhanced survival, regulated expression of cell-surface markers and induced chemotactic migration. These events appeared to be related to the NF-κB pathway. Stimulation with the Th2-like cytokines IL-5 and GM-CSF augmented NLR-mediated activation. These findings suggest the NLRs to be a new activation pathway for eosinophils and possibly a link between respiratory infections and allergic exacerbations. In the second part of the thesis (PAPERS IV-V), the clinical and cellular effects of ILIT are evaluated. Actively treated patients exhibited a clear improvement of their seasonal allergic symptoms as well as their nasal symptoms upon allergen challenge. The treatment increased the levels of allergen-specific IgE and decreased nasal inflammatory responses. On a cellular level, activation of CD4+ T cells and granulocytes was induced along with reduced Th2 and regulatory T lymphocyte activity. These findings appear to confirm ILIT as a safe and effective therapy for allergic rhinitis and reveal new insights on the cellular mechanisms underlying its beneficial effects. In summary, this thesis demonstrates a role for PRRs in lymphocytes and eosinophils and that ILIT is a safe and effective route that can be used for treating patients with allergic airway disorders. In the future, we hope that these findings can be used in the development of new and more effective treatment strategies for airway inflammation.
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| 5. |
- Niklasson, Terese, et al.
(författare)
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Mercury accumulation in fish in relation to abiotic characteristics and carbon source in a five-year old, Brazilian reservoir.
- 2006
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Ingår i: Abstracts of Eighth International Conference on Mercury as a Global Pollutant.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- It has frequently been reported that concentrations of mercury in fish increase significantly, often by three to four times, in recently constructed hydroelectric reservoirs. In the central-western parts of Brazil, a hydroelectric reservoir, called Lago Manso, was completed in 1999. Two previous studies concerning mercury levels in fish have been performed in the reservoir; one in 1999, before the construction of the dam and one in 2002, two years after completion of the reservoir. The objectives of this study were to continue to monitor the concentrations of mercury in fish in the reservoir as well as downstream, to determine the degree of bioaccumulation of mercury, and to identify groups of primary producers contributing energy to the fish food web. The effects of abiotic, physiological and ecological factors on the accumulation of mercury by fish examined. In total, 41 specimens of seven species; Brycon hilarii, Piaractusmesopotamicus, Serrasalmus marginatus, Serrasalmus spilopleura, Salminus brasiliensis, Pseudoplatystoma fasciatum, and Pseudoplatystoma corruscans, were analyzed for totalmercury content. The mercury levels were found to have increased drastically and were well above the dietary limits, recommended by WHO and FAO, for mercury in fish aimed at human consumption. Piscivorous Salminus brasiliensis, caught downstream, demonstrated the highest level of mercury, 1323 ng/g wet weight, followed by piscivorous Pseudoplatystoma fasciatum, 1204 ng/g wet weight, caught in the reservoir.The concentration varied widely between species, which could be related to differences in diet and trophic position. The degree of mercury accumulation in different species, shown by means of a bioconcentration factor (concentration in biota/concentration inwater), ranged between 4.08 and 5.93 log units. The most important groups of primary producers, determined by stable carbon isotope analysis (δ13C), appeared to be terrestrialC3 plants, aquatic macrophytes, and phytoplankton. A relationship was found between mercury concentration and carbon source but the mercury concentration in fish isprobably better explained by differences in trophic position. Dissolved organic carbon the water was shown to have increased slightly while dissolved oxygen had decreased, indicating enhanced transport, methylation, and bioavailability of mercury.
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| 6. |
- Tuomola, Leena, et al.
(författare)
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Fish mercury development in relation to abiotic characteristics and carbon sources in a six-year-old, Brazilian reservoir
- 2008
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 390:1, s. 177-187
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Tidskriftsartikel (refereegranskat)abstract
- Time series on fish mercury (Hg) development are rare for hydroelectric reservoirs in the tropics. In the central-western part of Brazil, a hydroelectric reservoir, called Lago Manso, was completed in 1999 after that background levels of fish Hg concentrations had been determined. The development for the first 3 years was studied in 2002. The objective of the present study was to determine development of fish Hg concentrations for a second threeyear period after flooding. The bioaccumulation factor and certain abiotic and biotic factors, possibly affecting the availability and accumulation of Hg, were also examined. The results show that Hg levels in fish from Lago Manso have increased more than five times compared to the background levels observed before construction of the reservoir. At the same time, dissolved organic carbon has increased while dissolved oxygen has decreased indicating enhanced bioavailability of Hg. In the reservoir, Salminus brasiliensis had in average a Hg content of 1.1 μg g−1 f.w., Pseudoplatystoma fasciatum 1.2, Serrasalmus marginatus/spilopleura 0.9, and Brycon hilarii 0.6 μg g−1 f.w. The average fish Hg contents were higher downstream, except for B. hilarii. In the reservoir, the average Hg content of each species was in 2005 always over the consumption limit (0.55 μg total Hg g−1 f.w.) recommended by WHO. Therefore, the people living around Lago Manso should be informed of the health effects of Hg, and fish consumption recommendations should be carried out. The accumulation of Hg varies widely between species as shown by the bioaccumulation factor which ranges between 5.08 and 5.59 log units. The observed variation is explained by differences in diet and trophic position with piscivorous fish exhibiting the highest mean Hg concentration, followed by carnivorous and omnivorous species. Carbon isotope analyses imply that trophic position is not the only cause of the observed differences in Hg levels between omnivorous B. hilarii, having a diet partly based on C4 plants, and carnivorous S. marginatus as well as piscivorous S. brasiliensis, whose carbon sources are depleted in 13C. The fact that the species have different carbon sources indicates that they belong to different food chains.
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