BACKGROUND Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. OBJECTIVE We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice. METHODS Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. RESULTS Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia, type-2 cytokines secretion, airway hyper-reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1-affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL-12/IFN-gamma axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. CONCLUSION Toll-like receptor 4 agonists co-adsorbed with allergen onto alum down-modulate allergic lung disease and prevent the development of polarized T cell-mediated airway inflammation.

/pdf/toll-like-receptor-4-agonists-adsorbed-to-aluminium-3vn73n6pf4.pdf

Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease: role of MyD88 adaptor molecule and interleukin-12/interferon-gamma axis.

Aluminium-containing adjuvants usually referred as Alum are considered as T helper type-2 (Th2) adjuvants, while agonists of toll-like receptors (TLR) are viewed as adjuvants that favor Th1/Th17 immunity. Alum has been used in numerous vaccine formulations, however its undesired pro-Th2 adjuvant activity constitutes a caveat for alum-based vaccines. Combining alum with TLR-dependent, pro-Th1/Th17 adjuvants might dampen the pro-Th2 activity and improve the effectiveness of vaccine formulations. Here, using the ovalbumin (OVA) model of allergic lung inflammation, we found that sensitization with the synthetic TLR9 agonist, which is composed of oligodeoxynucleotides containing CpG motifs adsorbed to Alum, inhibited the development of OVA-induced lung allergic Th2 responses without shifting towards a Th1-pattern. The conversion of T cell immunity from the polarized allergic Th2 response to a non-polarized form by sensitization with OVA/Alum/CpG was dependent on MyD88 signaling in myeloid cells. Notably, sensitization of IL-10-deficient mice with OVA/Alum/CpG resulted in the development of neutrophilic lung inflammation associated with IFNγ production. However, in IL-10/IL-12-deficient mice, it resulted in neutrophilic inflammation dominated by IL-17 production. We conclude that OVA/Alum/CpG sensitization signaling via MyD88 and IL-10 molecules results in non-polarized immunity. Conversely, OVA/Alum/CpG sensitization in presence of MyD88 but absence of IL-10 or IL-10/IL-12 molecules, results respectively in neutrophilic inflammation associated with IFNγ or IL-17 production. Our work provides novel OVA-models of lung inflammation and suggests that Alum/CpG-based formulations might be of potential use in anti-allergic or anti-infectious processes.

/pdf/cpg-odn-shapes-alum-adjuvant-activity-signaling-via-myd88-4zj1x77lzv.pdf

CpG-ODN Shapes Alum Adjuvant Activity Signaling via MyD88 and IL-10.

The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. Dexamethasone reduced BAL and lung tissue eosinophilia (ED50 values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED50 of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma.

/pdf/dissociation-by-steroids-of-eosinophilic-inflammation-from-1vlfc33zos.pdf

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways.

Toll-like receptors (TLRs) play a pivotal role in inflammatory processes, and individual TLRs have been investigated in nociception. We examined overlapping and diverging roles of spinal TLRs and their associated adaptor proteins in nociceptive processing. Intrathecal (IT) TLR2, TLR3, or TLR4 ligands (-L) evoked persistent (7-day) tactile allodynia (TA) that was abolished in respective TLR-deficient mice. Using Tnf(-/-) mice, we found that IT TLR2 and TLR4 TA was tumor necrosis factor (TNF) dependent, whereas TLR3 was TNF-independent. In Toll-interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP; Tirap(-/-)) mice (downstream to TLR2 and TLR4), allodynia after IT TLR2-L and TLR4-L was abolished. Unexpectedly, in TIR-domain-containing adapter-inducing interferon-β (Trif(lps2)) mice (downstream of TLR3 and TLR4), TLR3-L allodynia was abrogated, but intrathecal TLR4-L produced a persistent increase (>21days) in TA. Consistent with a role for interferon (IFN) β (downstream to TIR-domain-containing adapter-inducing IFNβ [TRIF]) in regulating recovery after IT TLR4-L, prolonged allodynia was noted in Ifnar1(-/-) mice. Further, IT IFNβ given to Trif(lps2) mice reduced TLR4 allodynia. Hence, spinal TIR domain-containing adaptor protein (TIRAP) and TRIF cascades differentially lead to robust TA by TNF-dependent and independent pathways, whereas activation of TRIF modulated processing through type I IFN receptors. Based on these results, we believe that processes leading to the activation of these spinal TLRs initiate TNF-dependent and -independent cascades, which contribute to the associated persistent pain state. In addition, TRIF pathways are able to modulate the TNF-dependent pain state through IFNβ.

Spinal toll-like receptor signaling and nociceptive processing: regulatory balance between TIRAP and TRIF cascades mediated by TNF and IFNβ.

Asthma is a highly prevalent, chronic respiratory disease that impacts millions of people worldwide and causes thousands of deaths every year. Asthmatics display different phenotypes with distinct genetic components, environmental causes, and immunopathologic signatures, and are broadly characterized into type 2-high or type 2-low (non-type 2) endotypes by linking clinical characteristics, steroid responsiveness, and molecular pathways. Regardless of asthma severity and adequate disease management, patients may experience acute exacerbations of symptoms and a loss of disease control, often triggered by respiratory infections. The interferon (IFN) family represents a group of cytokines that play a central role in the protection against and exacerbation of various infections and pathologies, including asthma. Type I and III IFNs in particular play an indispensable role in the host immune system to fight off pathogens, which seems to be altered in both pediatric and adult asthmatics. Impaired IFN production leaves asthmatics susceptible to infection and with uncontrolled type 2 immunity, promotes airway hyperresponsiveness (AHR), and inflammation which can lead to asthma exacerbations. However, IFN deficiency is not observed in all asthmatics, and alterations in IFN expression may be independent of type 2 immunity. In this review, we discuss the link between type I and III IFNs and asthma both in general and in specific contexts, including during viral infection, co-infection, and bacterial/fungal infection. We also highlight several studies which examine the potential role for type I and III IFNs as asthma-related therapies.

/pdf/insights-into-type-i-and-iii-interferons-in-asthma-and-1ytoofdwix.pdf

Insights Into Type I and III Interferons in Asthma and Exacerbations.

The effects of IFN-beta and prednisolone (Pred) on antigen-induced IgE antibody production, airway eosinophilia and airway hyperreactivity (AHR) were studied in ovalbumin-sensitized Balb/c mice. Three inhalations of antigen (ovalbumin) caused an increase in the number of eosinophils and lymphocytes in bronchoalveolar lavage fluid and AHR to acetylcholine with a significant elevation in the serum IgE level. IFN-beta clearly inhibited the antigen-induced airway inflammation and AHR, but did not affect IgE antibody production. Pred inhibited antigen-induced IgE antibody production, airway inflammation and AHR to acetylcholine. In addition, IFN-beta inhibited T-helper type 2 (Th2) cell clone (D10G4.1)-induced peritoneal eosinophilia in mice, but did not affect neutrophilia, whereas Pred inhibited D10G4.1-induced peritoneal eosinophilia and neutrophilia. These results suggest that IFN-beta inhibits antigen-induced bronchial inflammation and AHR probably due to the inhibition of Th2-induced airway eosinophilia.

Interferon-beta Prevents Antigen-induced Bronchial Inflammation and Airway Hyperreactivity in Mice.

The effect of a newly synthesized compound, HSR-609, on rat experimental rhinitis was investigated. In the first part of the study, a new experimental nasal allergic late phase eosinophilia model in Brown Norway (BN) rats was investigated. The increase in the number of antigen inhalations resulted in the proportional increase in the number of inflammatory cells such as macrophages, eosinophils and neutrophils in the nasal cavity lavage fluid (NCLF) at 5 h after each inhalation. The number of inflammatory cells reached a maximum 8 h after the antigen perfusion. Submaximum response was observed at 5 h after the antigen provocation. In this system, the serum IgG and IgE antibody titers measured by homologous passive cutaneous anaphylaxis were 160 and 640, respectively. In the second part of the study, the effects of prednisolone, cetirizine and a newly synthesized amphoteric antiallergic agent, HSR-609, on this allergic late nasal eosinophilia and neutrophilia in BN rats were investigated. Prednisolone and HSR-609 significantly inhibited the increase in the number of eosinophils in the NCLF but not cetirizine. Furthermore, prednisolone showed the inhibition of the increase in the number of macrophages and neutrophils in NCLF. These results suggest that this late phase eosinophilia model in the nose of BN rats may be useful for investigating the therapeutic drugs for nasal allergy and a newly synthesized amphoteric antiallergic agent, HSR-609, may be useful for the treatment of allergic rhinitis with eosinophilia.

Effects of an Amphoteric Antiallergic Agent, HSR-609,on Antigen-induced Late Phase Nasal Eosinophilia in Brown Norway Rats.

The effects of a newly synthesized anti-allergic agent, HSR-609, on allergic airway hyperresponsiveness and airway inflammation have been studied in sensitized mice. The effects were compared with those of two histamine H1 receptor antagonists, cetirizine and terfenadine, and prednisolone. Three inhalations of antigen caused an increase in leukocytes (including eosinophils) with increases in IL-5 in BALF and airway hyperresponsiveness to acetylcholine in BALB/c mice. All drugs were orally administered once a day for 10 days from the day before the first inhalation of antigen. HSR-609 (10 mg/kg) and prednisolone (5 mg/kg) significantly inhibited the antigen-induced airway hyperresponsiveness, whereas cetirizine (10 mg/kg) or terfenadine (100 mg/kg) did not affect this airway response. At the same time HSR-609 inhibited the antigen-induced eosinophilia and IL-5 production in BALF. Prednisolone also showed an inhibitory effect on the airway eosinophilia and IL-5 production but not cetirizine and terfenadine in the same experiments. In addition, HSR-609 (p.o.) dose-dependently suppressed the accumulation of eosinophils elicited by antigen-stimulated D10G4.1 cells, a murine Th2 clone, in peritoneal cavity lavage fluid in AKR/J mice. These results suggest that HSR-609 inhibits allergic airway hyperresponsiveness to acetylcholine probably because of the inhibition of Th2-dependent eosinophilia caused by IL-5. In addition, effects of HSR-609 were different from those of cetirizine and terfenadine concerning the inhibition of antigen-induced airway hyperresponsiveness in mice.

Effect of a Novel Anti-allergic Agent, HSR-609,on Antigen-induced Airway Hyperresponsiveness in Mice.

Effects of 11 histamine H1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined. The immediate phase reaction (IPR) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined. The inhibition of IPR by cetirizine and mequitazine were potent, but those by cyproheptadine and diphenhydramine were weak. The later phase reaction (LPR) assessed at 24 hours after antigen application was inhibited by chlorpheniramine, oxatomide, ketotifen, mequitazine, emedastine, terfenadine and azelastine. The inhibition of LPR by emedastine was potent, but those by ketotifen and terfenadine were only partial. Emedastine inhibited both IPR and LPR comparably. Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction, and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR. Histamine H1 receptor antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism, which may have an additional benefit for the treatment of allergic diseases.

Characterization of Antihistamines Using Biphasic Cutaneous Reaction in BALB/c Mice.

Experimental Study on Jet Blast at Laboratory Scale

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