Perspectives in asthma: Molecular use of microbial products in asthma prevention and treatment

Racila, Doina; Kline, Joel N.

doi:10.1016/j.jaci.2005.08.050

Cited by 63 publications

(41 citation statements)

References 18 publications

(14 reference statements)

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“…Currently there are phase 1 and 2 trials underway for treatment of a wide range of immune mediated conditions such as asthma, allergic rhinitis, and conjunctivitis. 36 Based on our results, the application of TLR9 agonists for immunotherapy may be associated with a risk of HSC differentiation and liver fibrosis. This risk is further accentuated by the known concentration of administered TLR9 agonists in the liver.…”

Section: Discussionmentioning

confidence: 71%

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

et al. 2007

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Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor ␤1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis.

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Section: Discussionmentioning

confidence: 71%

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

et al. 2007

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“…The hygiene hypothesis suggests that early-life environmental exposure to microbes or other pathogens and their products promotes innate immune responses that protect against the development of atopy and asthma (53). Many microorganisms have the ability to indirectly activate iNKT cells during infection (14,54), and some microbial glycolipid Ags were shown to directly activate iNKT cells (55)(56)(57)(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-γ Production

Matsuda

Takeda

Koya

et al. 2010

The Journal of Immunology

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Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA–α-galactosylceramide (OVA/αGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/αGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/αGalCer BMDCs into IFN-γ–deficient (IFN-γ−/−) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-γ treatment following OVA-BMDC transfer. Further, Jα18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/αGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-γ−/− mice restored the development of these responses in Jα18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/αGalCer BMDC transfer. iNKT cells from these IFN-γ−/− mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-γ as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.

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“…Recent strategies to treat allergic airway disease have focused on limiting or reducing Th2 inflammation. One immunotherapeutic strategy being developed for clinical therapy in asthma involves the use of hypomethylated oligodeoxynucleotides (ODNs) containing CpG motifs, which mimic either bacterial or viral DNA [3,4,5]. Prophylactic, systemic CpG administration in acute allergic airway models driven by ovalbumin (OVA), Aspergillus antigen, or house dust mite elicits major protective effects [6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Intranasal CpG Therapy Attenuated Experimental Fungal Asthma in a TLR9-Dependent and -Independent Manner

Ramaprakash¹,

Hogaboam²

2009

Int Arch Allergy Immunol

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Background: CpG administration abolishes airway inflammation and remodeling in acute models of allergic airway disease. Methods: Herein, we investigated the therapeutic effect of CpG in a chronic fungal model of asthma. TLR9+/+ and TLR9–/– mice were sensitized to soluble Aspergillus fumigatus antigens and challenged with live A. fumigatus conidia. Mice were treated with intraperitoneal (IP) or intranasal (IN) CpG, or left untreated 14–28 days after conidium challenge. All features of allergic airway disease were attenuated in TLR9+/+ mice treated with IN CpG, including airway hyperresponsiveness (AHR), mucus production, and peribronchial fibrosis. Results: TLR9–/– mice treated with IN CpG exhibited attenuated airway remodeling but not AHR. Whole-lung IL-12 levels were significantly elevated in both TLR9+/+ and TLR9–/– mice receiving IN CpG but not in either group receiving IP CpG. Whole-lung IL-10 levels were significantly elevated in IN CpG-treated TLR9+/+ mice but not in TLR9–/– mice receiving IN CpG. Increased whole-lung transcript and protein levels of the scavenger receptors SR-A and MARCO were observed in TLR9–/– mice compared with TLR9+/+ mice, possibly accounting for the CpG responsiveness in the knockout group. Conclusions: Together, these data show that IN CpG has a therapeutic effect during established fungal asthma, which is TLR9 dependent and independent.

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Perspectives in asthma: Molecular use of microbial products in asthma prevention and treatment

Cited by 63 publications

References 18 publications

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-γ Production

Intranasal CpG Therapy Attenuated Experimental Fungal Asthma in a TLR9-Dependent and -Independent Manner

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