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Lee C.C.,China Medical University at Taichung | Ho H.,Graduate Institute of Immunology | Lee K.T.,Institute of Microbiology and Biochemistry | Jeng S.T.,National Taiwan University | And 4 more authors.
Cellular and Molecular Immunology

In clinical therapy, the amount of antigen administered to achieve oral tolerance for allergic diseases is large, and the cost is a major consideration. In this study, we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy, and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived antigen. We used plants (tobacco leaves) transgenic for the Dermatophagoides pteronyssinus 2 (Der p2) antigen to produce Der p2. Mice received total protein extract from Der p2 orally once per day over 6 days (days 0-2 and days 6-8). Mice were also sensitized and challenged with yeast-derived recombinant Der p2 (rDer p2), after which the mice were examined for airway hyper-responsiveness and airway inflammation. After sensitization and challenge with rDer p2, mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers, decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid, and eosinophil infiltration in the airway. In addition, hyper-responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants, and CD4 CD25 Foxp3 regulatory T cells were significantly increased in mediastinal and mesenteric lymph nodes. Furthermore, splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer p2. The data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases. © 2011 CSI and USTC. All rights reserved. Source

Wang W.-B.,National Health Research Institute | Yen M.-L.,National Taiwan University Hospital | Liu K.-J.,National Institute of Cancer Research | Liu K.-J.,Taipei Medical University | And 7 more authors.
Stem Cell Reports

Summary Multipotent human mesenchymal stromal cells (hMSCs) harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A)-secreting T (Th17) lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25 - also known as IL-17E - as well as programmed death ligand-1 (PD-L1), a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.In this article, Yen and colleagues demonstrate that multipotent human mesenchymal stromal cells (hMSCs) suppress interleukin (IL)-17A-secreting T cell (Th17) responses through expression of IL-25, a paracrine factor, and programmed death ligand-1 (PD-L1), a cell surface ligand. The requirement of both factors is explained by IL-25 modulation of PD-L1 expression via JNK and STAT3 to orchestrate an overall effect of suppressing Th17 responses. © 2015 The Authors. Source

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