Suppression of allergic airway disease using mycobacterial lipoglycans

Sayers, Ian; Severn, Wayne B.; Scanga, Connie B.; Hudson, J D; Gros, Graham Le; Harper, Jacquie L.

doi:10.1016/j.jaci.2004.03.057

Cited by 50 publications

(69 citation statements)

References 35 publications

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“…Furthermore, PIMs have been reported to suppress allergic airway disease, which is associated with increased production of IL-10 (2, 63). However, PIM 1 and PIM 2 were used in the latter two studies (2,63) and IL-10 induction in this case likely involves a different pathway (22). In our experiments, in which LPS-primed MoDCs were cocultured with wild-type M. bovis BCG or the ⌬pimE and ⌬pimE ⌬capA mutant strains, no decrease in IL-10 secretion by MoDCs incubated with the mutant strains compared to wild-type M. bovis BCG was found (Fig.…”

Section: Discussionmentioning

confidence: 63%

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

et al. 2009

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The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM 6 , which contains terminal ␣(132)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di-and tetramannosylated PIM 2 and PIM 4 , respectively. To determine the role of PIM 6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guérin deficient in the production of PIM 6 (⌬pimE) was created, as well as a double knockout deficient in the production of both PIM 6 and the mannose caps on LAM (⌬pimE ⌬capA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM 6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.

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Section: Discussionmentioning

confidence: 63%

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

et al. 2009

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“…Mycobacterial cell wall components (lipoglycans lipoarabinomannan, and phosphatidylinositol mannan) also have been shown to suppress AAD; however, their effects on AHR have not been determined (38). Furthermore, mycobacterial phosphatidylinositol mannoside has been reported to bind CD1d and activate human and mouse NKT cells, which may be a problem for the therapeutic use of mycobacterial components (39).…”

Section: Discussionmentioning

confidence: 99%

Components of Streptococcus pneumoniae Suppress Allergic Airways Disease and NKT Cells by Inducing Regulatory T Cells

Thorburn

Foster

Gibson

et al. 2012

The Journal of Immunology

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Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells.

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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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Suppression of allergic airway disease using mycobacterial lipoglycans

Cited by 50 publications

References 35 publications

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

Components of Streptococcus pneumoniae Suppress Allergic Airways Disease and NKT Cells by Inducing Regulatory T Cells

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

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