scholarly journals Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism

2015 ◽  
Vol 309 (10) ◽  
pp. L1208-L1218 ◽  
Author(s):  
Timothy P. Moran ◽  
Keiko Nakano ◽  
Gregory S. Whitehead ◽  
Seddon Y. Thomas ◽  
Donald N. Cook ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Allergic Asthma ◽  
House Dust ◽  
Lavage Fluid ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cell Responses ◽  
Th2 Responses ◽  
Th2 Differentiation

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

scholarly journals Fms-Like Tyrosine Kinase 3-Independent Dendritic Cells Are Major Mediators of Th2 Immune Responses in Allergen-Induced Asthmatic Mice

2020 ◽  
Vol 21 (24) ◽  
pp. 9508
Author(s):  
Sang Chul Park ◽  
Dahee Shim ◽  
Hongmin Kim ◽  
Yeeun Bak ◽  
Da Yeon Choi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Tyrosine Kinase ◽  
Allergic Asthma ◽  
Lung Inflammation ◽  
In Vivo Models ◽  
Allergic Lung Inflammation ◽  
Th2 Responses

Dendritic cells (DCs) are the main mediators of Th2 immune responses in allergic asthma, and Fms-like tyrosine kinase 3 ligand (Flt3L) is an important growth factor for the development and homeostasis of DCs. This study identified the DC populations that primarily cause the initiation and development of allergic lung inflammation using Fms-like tyrosine kinase 3 (Flt3) knockout (KO) mice with allergen-induced allergic asthma. We observed type 2 allergic lung inflammation with goblet cell hyperplasia in Flt3 KO mice, despite a significant reduction in total DCs, particularly CD103+ DCs, which was barely detected. In addition, bone marrow-derived dendritic cells (BMDCs) from Flt3 KO mice directed Th2 immune responses in vitro, and the adoptive transfer of these BMDCs exacerbated allergic asthma with more marked Th2 responses than that of BMDCs from wild-type (WT) mice. Furthermore, we found that Flt3L regulated the in vitro expression of OX40 ligand (OX40L) in DCs, which is correlated with DC phenotype in in vivo models. In conclusion, we revealed that Flt3-independent CD11b+ DCs direct Th2 responses with the elevated OX40L and are the primary cause of allergic asthma. Our findings suggest that Flt3 is required to control type 2 allergic inflammation.

scholarly journals Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 277
Author(s):  
Magdalena Kowalewicz-Kulbat ◽  
Piotr Szpakowski ◽  
Krzysztof T. Krawczyk ◽  
Marek L. Kowalski ◽  
Slawomir Kosinski ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Allergic Asthma ◽  
House Dust ◽  
Inflammatory Diseases ◽  
House Dust Mites ◽  
Th2 Cells ◽  
Der P 1 ◽  
Therapeutic Tools ◽  
Recombinant Bcg

The only currently available anti-tuberculosis vaccine, Bacillus Calmette–Guérin (BCG), has been reported to also protect against unrelated diseases, including inflammatory diseases such as allergic asthma. Recombinant BCG strains that produce IL-18 have been shown to enhance Th1 responses over non-recombinant BCG and to reduce IL-5 production and bronchoalveolar eosinophilia in mice. However, their ability to decrease the immune polarization of human Th2 cells is not known. Here, we show that BCG and recombinant BCG producing human IL-18 (rBCG-hIL-18) induced the maturation of Der p 1-stimulated monocyte-derived dendritic cells (MD-DCs) from healthy controls and from patients allergic to house dust mites. After incubation with mycobacteria and Der p 1, MD-DCs produced significantly more IL-23 and IP-10 but had no effect on IL-12p70 or IL-10 production compared to Der p 1-pulsed MD-DCs in the absence of mycobacteria. In the presence of Der p 1, BCG- and rBCG-hIL-18-pulsed MD-DCs cocultured with naive, but not with memory T cells from allergic patients, resulted in a decrease in IL-5 production compared to non-pulsed MD-DCs cultured in the presence of Der p 1. BCG, and especially rBCG-hIL-18, may thus be potential therapeutic tools to reduce exacerbated Th2 responses in patients with allergic asthma.

scholarly journals TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

2005 ◽  
Vol 202 (9) ◽  
pp. 1213-1223 ◽  
Author(s):  
Tomoki Ito ◽  
Yui-Hsi Wang ◽  
Omar Duramad ◽  
Toshiyuki Hori ◽  
Guy J. Delespesse ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Th2 Cells ◽  
T Helper ◽  
Cell Responses ◽  
Th Cell ◽  
Tnf Α ◽  
Ox40 Ligand ◽  
Helper Type

We recently showed that dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) prime naive CD4+ T cells to differentiate into T helper type 2 (Th2) cells that produced high amounts of tumor necrosis factor-α (TNF-α), but no interleukin (IL)-10. Here we report that TSLP induced human DCs to express OX40 ligand (OX40L) but not IL-12. TSLP-induced OX40L on DCs was required for triggering naive CD4+ T cells to produce IL-4, -5, and -13. We further revealed the following three novel functional properties of OX40L: (a) OX40L selectively promoted TNF-α, but inhibited IL-10 production in developing Th2 cells; (b) OX40L lost the ability to polarize Th2 cells in the presence of IL-12; and (c) OX40L exacerbated IL-12–induced Th1 cell inflammation by promoting TNF-α, while inhibiting IL-10. We conclude that OX40L on TSLP-activated DCs triggers Th2 cell polarization in the absence of IL-12, and propose that OX40L can switch IL-10–producing regulatory Th cell responses into TNF-α–producing inflammatory Th cell responses.

scholarly journals IgM regulates airway hyperresponsiveness via modulation of actin associated genes.

2021 ◽  
Author(s):  
SABELO HADEBE ◽  
Anca Flavia Savulescu ◽  
Jermaine Khumalo ◽  
Katelyn Jones ◽  
Sandisiwe Mangali ◽  
...  
Keyword(s):  
B Cells ◽  
Allergic Asthma ◽  
Airway Hyperresponsiveness ◽  
Angiogenesis Inhibitor ◽  
Erythroid Differentiation ◽  
Immunoglobulin M ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Current Therapies ◽  
Cell Force

Abstract Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model by sensitising wild type (WT) and IgM-deficient (IgM-/-) mice with HDM. We validated our findings using CRISPR and single cell force cytometry in human ASM. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and erythroid differentiation regulator 1 (Erdr1). Deletion of BAIAP2L1 and ERDR1 reduced human ASM contraction when stimulated with TNF-α. These are unprecedented findings and have implications in future treatment of asthma beyond current therapies.

scholarly journals Biologic targeted therapy in allergic asthma

2019 ◽  
Vol 2 (1) ◽  
pp. 24-34
Author(s):  
Kevin Kron ◽  
Mason J. Crow ◽  
Ali Olyaei ◽  
Anthony Montanaro
Keyword(s):  
Clinical Trials ◽  
Allergic Asthma ◽  
Immunoglobulin E ◽  
Treatment Options ◽  
Signs And Symptoms ◽  
Biologic Agents ◽  
Clinical Severity ◽  
Th2 Cells ◽  
Dosing Regimens

Background: Asthma is a heterogeneous inflammatory disease of the airway, characterized by airway hyperresponsiveness, airway obstruction, mucus hyperproduction, and airway-wall remodeling. Management of this disease involves the use of several types of therapeutic agents, each with unique indications based on the underlying cause of inflammation, clinical severity, and patient phenotype and/or endotype. Objective: A review of the function, clinical utility, and safety of biologic agents in the management of allergic asthma. This particular asthma phenotype involves multiple cytokines in its pathogenesis, specifically those secreted by T-helper type 2 cells. Methods: Medical literature was obtained from online biomedical archive searches from July 2018 to May 2019. An emphasis was placed on clinical trials that discussed biologic agents that target immunoglobulin E, interleukin (IL) 5, IL-4/IL-13, and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) pathways involved in the expression of allergic asthma. Results: The treatment options reviewed in this article were shown to be effective in targeting these pathways associated with allergic asthma. However, because these biologic agents are commonly prescribed in the treatment of severe asthma, many patients continue to experience asthma signs and symptoms. Conclusion: Future clinical trials that study these agents should focus on ideal patient selection, dosing regimens, and cost-effectiveness in the management of asthma. Ideally, comparative trials should be undertaken to assist the clinician in choosing the optimal agent.

Sign in / Sign up

Export Citation Format

Share Document