TLR9-Based Immunotherapy for the Treatment of Allergic Diseases

Farrokhi, Shokrollah; Abbasirad, Narjes; Movahed, Ali; Pishjoo, Masoud; Rezaei, Nima

doi:10.2217/imt-2016-0104

Cited by 23 publications

(19 citation statements)

References 70 publications

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“…An allergic airway disease is usually dominated by a strong Th2 response which can be redirected to Th1 response by regulation of TLRs signaling (4,31,32), making TLRs attractive therapeutic targets. During the last decade, accumulating evidence has been focused on the role of TLRs in the pathogenesis of airway inflammatory diseases such as asthma and the possibility of using TLRs-based therapies for asthma (33,34). To date, TLR2 has been considered as the most relevant to the onset of asthma.…”

Section: Discussionmentioning

confidence: 99%

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

Zhao

Xie

et al. 2020

Front. Immunol.

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Toll-like receptor 2 (TLR2) is suggested to initiate the activation of NLRP3 inflammasome, and considered to be involved in asthma. The findings that melatonin modulates TLRs-mediated immune responses, together with the suppressing effect of TLRs on endogenous melatonin synthesis, support the possibility that a feedback loop exists between TLRs system and endogenous melatonin synthesis. To determine whether TLR2-melatonin feedback loop exists in allergic airway disease and regulates NLRP3 inflammasome activity, wild-type (WT) and TLR2 −/− mice were challenged with OVA to establish allergic airway disease model. Following OVA challenge, WT mice exhibited increased-expression of TLR2, activation of NLRP3 inflammasome and marked airway inflammation, which were all effectively inhibited in the TLR2 −/− mice, indicating that TLR2-NLRP3 mediated airway inflammation. Meanwhile, melatonin biosynthesis was reduced in OVA-challenged WT mice, while such reduction was notably rescued by TLR2 deficiency, suggesting that TLR2-NLRP3-mediated allergic airway inflammation was associated with decreased endogenous melatonin biosynthesis. Furthermore, addition of melatonin to OVA-challenged WT mice pronouncedly ameliorated airway inflammation, decreased TLR2 expression and NLRP3 inflammasome activation, further implying that melatonin in turn inhibited airway inflammation via suppressing TLR2-NLRP3 signal. Most interestingly, although melatonin receptor antagonist luzindole significantly reduced the protein expressions of ASMT, AANAT and subsequent level of melatonin in OVA-challenged TLR2 −/− mice, it exhibited null effect on leukocytes infiltration, Th2-cytokines production and NLRP3 activity. These results indicate that a TLR2-melatonin feedback loop regulates NLRP3 inflammasome activity in allergic airway inflammation, and melatonin may be a promising therapeutic medicine for airway inflammatory diseases such as asthma.

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Section: Discussionmentioning

confidence: 99%

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

Zhao

Xie

et al. 2020

Front. Immunol.

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“…Furthmore, the TLR9 also expresses on the suface of osteocytes to regulate bone metabolism [3]. Agents involved in lipopolysaccharide signal transduction pathways induced by TLR has been proposed to be potential strategy for treating inflammation disease, such as allergic diseases [4]. Due to the significance of TLR on inflammatory and bone formation, we hyperthesized that agents that could target TLR might also have potential for treating periodontitis.…”

Section: Introductionmentioning

confidence: 99%

The Toll-like receptor ligand, CpG oligodeoxynucleotides, regulate proliferation and osteogenic differentiation of osteoblast

Zheng

et al. 2020

J Orthop Surg Res

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Background: This study aimed to investigate the regulation of CpG oligodeoxynucleotides (ODNs) on proliferation and osteogenic differentiation of MC3T3 cells. Methods: The laser co-focusing and flow cytometry assay were employed to detect cell uptake of CpG ODN 2006. Twelve ODNs were sythesized, and their effects on proliferation and differentiation were detected by MTT and alkaline phosphatase (ALP) activity assay. Flow cytometry assay was used to examine the regulation of CpG ODN on cell cycle. Quantitative real-time PCR (qRT-PCR) and western blot were used to evaluate the regulation of CpG ODN on mRNA and protein expression of osteogenic differentiation genes. Results: The phosphorothioate CpG ODN 2006 could efficiently enter the MC3T3 cells in 1 h and locate in the cytoplasm. The MTT assay demonstrated CpG ODNs could promote MC3T3 cell proliferation and differentiation in the early stage, and gradually attenuated along with the increase of treating time, except for BW001 and FC001. qRT-PCR assay demonstrated that all the 12 CpG ODNs could promote the relative expression level of osteogenic differentiated genes, SP7 and OCN. In addition, western blot analysis suggested the CpG ODNs of BW001 and FC001 could increase the protein expression of P27 Kip1 and Runx2 and decrease the protein expression of cyclin D1. Conclusion: The selected CpGODNs may be a potential gene therapy for bone regeneration of periodontitis.

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“…In human medicine, CpG administration has been shown to reduce Th2 immune response and activate T regulatory cells. 35 On the immunological level, a significant decrease of the Th2 cytokine IL-4 and the Th1 cytokine IFN-γ was indicated. The mRNA analysis showed that the CpG therapy resulted in a decrease of IL-8, T-bet, and GATA-3-mRNA expression.…”

Section: Discussionmentioning

confidence: 98%

Immunomodulatory asthma therapy in the equine animal model: A dose‐response study and evaluation of a long‐term effect

Klier

Bartl

Geuder

et al. 2019

Immunity Inflam & Disease

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Introduction Equine asthma represents a naturally occurring animal model for human allergic neutrophilic asthma. Inhalative nanoparticle‐bound cytosine‐phosphate‐guanosine (CpG‐GNP) immunotherapy, independent of specific allergens, has already shown promising clinical and immunological results in previous studies and offers the possibility to treat the underlying cause of the disease. This study analyses the relationship between dose and response, and evaluates a possible long‐term effect. Methods In the prospective, randomised, double‐blind clinical field study, 29 horses suffering from equine asthma received 10 inhalation treatments with either 187.5 µg CpG‐GNP (CpG single dose [CpGsd]; n = 11), 375 µg CpG‐GNP double dose (CpG double dose [CpGdd]; n = 9) (q48h for 20 days) or 1600 µg beclomethasone (n = 9) (q24h for 10 days). Each horse was examined three times: before the treatment (I), immediately after the 10 inhalations (II), and 8 weeks after the final inhalation (III). The three groups were compared according to clinical and laboratory parameters. The study examined the sustainability of the long‐term effect of the treatment after 8 weeks, as well as the tolerability of the formula as a double dose. Results The CpGsd resulted in a significant improvement in 82% of the parameters, the CpGdd in 72%. In the long‐term evaluation, the CpGsd showed a significant improvement in 100% of the parameters in comparison to the initial values, the CpGdd in 67%. On the immunological level, the bronchoalveolar lavage revealed a significant reduction of IL‐4, IL‐8, and interferon‐γ. Conclusion Both CpG groups displayed significant improvements in clinical and laboratory parameters, especially regarding the long‐term effect of CpGsd. Doubling the CpG dose did not result in any improvement in comparison to the original single dose. On the immunological level, an anti‐inflammatory, as well as an immunomodulatory effect, apart from a Th2‐dominated immune response, could be observed. This immunomodulatory inhalation treatment could indicate a new possibility for human allergic asthma therapy.

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TLR9-Based Immunotherapy for the Treatment of Allergic Diseases

Cited by 23 publications

References 70 publications

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

The Toll-like receptor ligand, CpG oligodeoxynucleotides, regulate proliferation and osteogenic differentiation of osteoblast

Immunomodulatory asthma therapy in the equine animal model: A dose‐response study and evaluation of a long‐term effect

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