The Toll-Like Receptor-2/6 Agonist Macrophage-Activating Lipopeptide-2 Cooperates with IFN-γ to Reverse the Th2 Skew in an In Vitro Allergy Model

Weigt, Henning; Mühlradt, Peter F.; Larbig, Michael; Krug, Norbert; Braun, Armin

doi:10.4049/jimmunol.172.10.6080

Cited by 36 publications

(24 citation statements)

References 42 publications

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“…Generating DC from murine bone marrow CD34 + HPC has been used as an alternative, but this procedure is time-consuming and requires a significant number of animals. The establishment of human in vitro models of DC had offered the possibility to demonstrate that haptens were able to directly activate cultured DC derived from peripheral blood monocytes or from CD34 + HPC (Aiba et al, 1997;Degwert et al, 1997;Rougier et al, 2000;De Smedt et al, 2001;Weigt et al, 2004). Several studies confirmed these observations showing the upregulation of maturation markers (CD83, CD80, CD86, CD40) on human DC (Coutant et al, 1999;Aiba et al, 2000;Tuschl et al, 2000;Arrighi et al, 2001).…”

Section: Use Of Dcs To Identify Contact Allergenssupporting

confidence: 65%

Present and future ofin vitroimmunotoxicology in drug development

Galbiati

Mitjans

Corsini

2010

Journal of Immunotoxicology

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Section: Use Of Dcs To Identify Contact Allergenssupporting

confidence: 65%

Present and future ofin vitroimmunotoxicology in drug development

Galbiati

Mitjans

Corsini

2010

Journal of Immunotoxicology

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“…Although numerous reported epidemiological and experimental studies have demonstrated the inhibitory role of live or killed microbes or microbial components on allergic responses [18][19][20][21][22][23][24][25], the basis for this inhibition remains unclear. In particular, little experimental study has been performed on the effect and mechanism of neonatal microbial exposure on airway allergic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Imprinted DC mediate the immune‐educating effect of early‐life microbial exposure

et al. 2009

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It has been long proposed that exposure to environmental factors early in life may have an educating effect on the development of immune regulatory functions. However, experimental studies on this issue are limited and the related molecular and cellular basis remains unclear. Here we report that neonatal exposure to killed bacteria (Chlamydia muridarum, originally called Chlamydia trachomatis mouse pneumonitis (MoPn)) changed the pattern of the hosts' immune responses to a model allergen (OVA) in adulthood. This was associated with altered phenotype and function of DC. We found that DC from adult mice treated neonatally with UV-killed MoPn exhibited distinct patterns of surface marker and TLR expression and cytokine production from control mice (DC from adult mice neonatally treated with vehicle, (Sham-DC)). More importantly, DC from adult mice treated neonatally with UV-killed MoPn induced significantly lower type-2 antigen-specific T-cell responses than Sham-DC shown in DC:T co-culture experiments in vitro and in adoptive transfer experiments in vivo. In addition, depletion of T cells in vivo largely abolished the phenotypic and functional alterations of DC caused by bacterial exposure, suggesting the involvement of T cell in this process. Our study demonstrates a central role of DC in linking the early-life exposure to microbial products and the balanced development of immune regulatory functions and the involvement of T cells in imprinting of the DC function.Key words: Allergy . DC . Hygiene hypothesis . IL-10 . TLR IntroductionThe immune system of a host experiences multiple influences from the outside world during development from birth to adult life. Numerous studies have demonstrated that environmental factors encountered during the developmental stage have considerable effect in shaping the pattern of immune responses in adult life. Therefore, the exposure to ''proper'' environmental antigens in early life might be important for the formation and maintenance of a balanced immune regulatory system in the host, thus preventing autoimmunity and allergic diseases [1,2].Over the past decades, the general burden of infections in the developed areas of the world has been reduced due to a better hygiene, and the ''hygiene hypothesis'' has been raised to explain the significant increase of allergic diseases [3,4]. Specifically, it has been hypothesized that exposure to microbial products during early childhood may have an inhibitory effect on the development of allergic diseases [4][5][6]. Notably, in a series of well-performed epidemiological studies on children of European farmers (Allergy and Endotoxin), it was demonstrated that children who grew up in a farming environment and had close contact with farm animals exhibited significantly low levels of allergy and asthma in later life [7][8][9]. However, the proposed educating effect of exposure to various microbial products during early life on the development of immune regulatory function has not been tested in detail using experimental approaches. 469More i...

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“…MALP-2 can induce CD80 (B7-1), CD86 (B7-2), major histocompatibility complex I and II and CD40 expression in B cells and dendritic cells (DCs) [51,52]. Furthermore, MALP-2 has the ability to increase the release of interferon-γ (IFN-γ) from DCs in response to allergens [53]. Mucosal delivery of MALP-2 via the intratracheal route resulted in a marked decrease in AHR, eosinophilia and Th2 cytokines in a murine model of asthma [54].…”

Section: Tlr1 2 6 and 10mentioning

confidence: 99%

A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

Aryan

Holgate

Radzioch

et al. 2014

Int Arch Allergy Immunol

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Toll-like receptors (TLR) belong to a large family of pattern recognition receptors known as the ancient ‘gatekeepers' of the immune system. TLRs are located at the first line of defense against invading pathogens as well as aeroallergens, making them interesting targets to modulate the natural history of respiratory allergy. Agonists of TLRs have been widely employed in therapeutic or prophylactic preparations useful for asthma/allergic rhinitis (AR) patients. MPL® (a TLR4 agonist) and the CpG oligodeoxynucleotide of 1018 ISS, a TLR9 agonist, show strong immunogenicity effects that make them appropriate adjuvants for allergy vaccines. Targeting the TLRs can enhance the efficacy of specific allergen immunotherapy, currently the only available ‘curative' treatment for respiratory allergies. In addition, intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics have revealed efficacy in the relief of the symptoms of AR patients. No anaphylaxis has been so far reported with such compounds targeting TLRs, with the most common adverse effects being transient and local irritation (e.g. redness, swelling and pruritus). Many other compounds that target TLRs have been found to suppress airway inflammation, eosinophilia and airway hyper-responsiveness in various animal models of allergic inflammation. Indeed, in the future a wide variability of TLR agonists and even antagonists that exhibit anti-asthma/AR effects are likely to emerge.

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The Toll-Like Receptor-2/6 Agonist Macrophage-Activating Lipopeptide-2 Cooperates with IFN-γ to Reverse the Th2 Skew in an In Vitro Allergy Model

Cited by 36 publications

References 42 publications

Present and future ofin vitroimmunotoxicology in drug development

Present and future ofin vitroimmunotoxicology in drug development

Imprinted DC mediate the immune‐educating effect of early‐life microbial exposure

A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

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