The Mannose Receptor Mediates the Uptake of Diverse Native Allergens by Dendritic Cells and Determines Allergen-Induced T Cell Polarization through Modulation of IDO Activity

Royer, Pierre‐Joseph; Emara, Mohamed; Yang, Chyun-Yu; Al-Ghouleh, Abeer; Tighe, Patrick J.; Jones, Nick D.; Sewell, Herb F.; Shakib, F; Martı́nez-Pomares, Luisa; Ghaemmaghami, Amir M.

doi:10.4049/jimmunol.1000774

Cited by 162 publications

(183 citation statements)

References 52 publications

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“…These receptors have been described in oral DCs as well,35 including the CD11b + cells involved in tolerance induction during SLIT 21. Interestingly, IL‐4 may increase the expression of the mannose receptor on myeloid cells,36 a fact already reported in DCs from allergy patients,37 thus opening the possibility of even a better uptake of PM‐allergoids in these patients. A relevant point of the present study is that the cells used for allergen uptake were resident cells obtained directly from the oral mucosa in a steady‐state situation.…”

Section: Discussionmentioning

confidence: 86%

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice

Soria

López-Relaño

Viñuela

et al. 2018

Allergy

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BackgroundPolymerized allergoids coupled to nonoxidized mannan (PM‐allergoids) may represent novel vaccines targeting dendritic cells (DCs). PM‐allergoids are better captured by DCs than native allergens and favor Th1/Treg cell responses upon subcutaneous injection. Herein we have studied in mice the in vivo immunogenicity of PM‐allergoids administered sublingually in comparison with native allergens.MethodsThree immunization protocols (4‐8 weeks long) were used in Balb/c mice. Serum antibody levels were tested by ELISA. Cell responses (proliferation, cytokines, and Tregs) were assayed by flow cytometry in spleen and lymph nodes (LNs). Allergen uptake was measured by flow cytometry in myeloid sublingual cells.ResultsA quick antibody response and higher IgG2a/IgE ratio were observed with PM‐allergoids. Moreover, stronger specific proliferative responses were seen in both submandibular LNs and spleen cells assayed in vitro. This was accompanied by a higher IFNγ/IL‐4 ratio with a quick IL‐10 production by submandibular LN cells. An increase in CD4+ CD25high FOXP3+ Treg cells was detected in LNs and spleen of mice treated with PM‐allergoids. These allergoids were better captured than native allergens by antigen‐presenting (CD45+ MHC‐II +) cells obtained from the sublingual mucosa, including DCs (CD11b+) and macrophages (CD64+). Importantly, all the differential effects induced by PM‐allergoids were abolished when using oxidized instead of nonoxidized PM‐allergoids.ConclusionOur results demonstrate for the first time that PM‐allergoids administered through the sublingual route promote the generation of Th1 and FOXP3+ Treg cells in a greater extent than native allergens by mechanisms that might well involve their better uptake by oral antigen‐presenting cells.

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Section: Discussionmentioning

confidence: 86%

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice

Soria

López-Relaño

Viñuela

et al. 2018

Allergy

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“…The cysteine-rich domain recognizes sulphated sugars, whereas the recognition of mannose, fucose and N-acetylglucosamine is mediated by multiple CRDs [34]. Several allergens such as Der p 1 and Der p 2 (house dust mite, HDM), Bla g 2 (cockroach), Ara h 1 (peanut), Can f 1 (dog) and Fel d 1 (cat) appear to bind to CRDs of MR through their carbohydrate moieties [35][36][37]. MR may be involved not only in delivering allergens to the antigen-presenting pathway [38], but also in directing DC conditioning for Th2 cell priming.…”

Section: C-type Lectinsmentioning

confidence: 99%

What makes an allergen?

Scheurer

Toda

Vieths

2015

Clin Experimental Allergy

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SummaryAllergic diseases are an immune disorder reacting to certain type of allergen(s). Remarkably only a small number of proteins of the plant and animal proteome act as allergens. Therefore, allergens have been clustered according to their common structural, biochemical and functional features. Evidence has accumulated that some allergens possess intrinsic adjuvant properties to stimulate the innate immunity. The adjuvant properties appear to contribute to the allergenicity of the respective proteins, namely the ability to cause allergic sensitization in susceptible subjects or allergic reactions in sensitized individuals. Here, we discuss how allergens interact with the innate immune cells, in particular dendritic cells and epithelial cells, via binding to pattern recognition receptors, exhibiting proteolytic activities and/or inducting type 2 innate lymphoid cells (ILC2), thereby contributing to the sensitization and development of allergic diseases.

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“…Development of a glycosylated subunit vaccine that contained glycan moieties could potentially enable the targeting of a specific receptor [10]. Glycosylated proteins and peptides have been investigated for MR targeting for vaccine development purposes.…”

Section: Subunit Vaccines For Targeting the Mannose Receptormentioning

confidence: 99%

“…Glycosylated proteins and peptides have been investigated for MR targeting for vaccine development purposes. To date, mannan and mannosylated antigens are one of the most effective ligands for targeting the MR and eliciting an immune response as a result of mannan's strong ability to compete with other ligands for receptor binding [10,[83][84][85][86][87]]. …”

Section: Subunit Vaccines For Targeting the Mannose Receptormentioning

confidence: 99%

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Mannosylated lipopetides as model vaccines for targeting the mannose receptor

Sedaghat¹

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The mannose receptor (MR) is an important component of the immune system and understanding the structural and conformational characteristics of this receptor is a key aspect of targeted vaccine design. Improved understanding of the role of carbohydrate recognition domains (CRDs) 4-7 in recognising glycosylated ligands present on the surface of pathogens such as C. albicans, P. carinii, L. donovani, and M. tuberculosis has given new insight into MR vaccine development. Initial studies identified mannan and its derivatives to be important ligands in MR targeting, providing essential knowledge about structural properties of the MR. During the last decade many attempts have been made to target this receptor for applications including vaccine and drug development.In the present study, a library of vaccine constructs comprising fluorescently-labelled mannosylated lipid dendrimers that contained the ovalbumin CD4 + epitope, OVA323-339, as the model peptide antigen were synthesised using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in antigen presenting cells.Mannosylated building blocks were prepared with a Lewis acid reaction and the reaction was successfully modified and monitored for a better yield. This was followed by solid phase synthesis of mannosylated peptides with an azide functional group and a fluorescent tag. Considering the presence of multi-components on the designed mannosylated peptide, different methods of preparation was used and a high yield of the final mannosylated peptides with an azide functional group and a fluorescent tag were prepared. Further, OVA323-339 lipopeptides with an alkyne functional group were prepared using microwave assisted peptide synthesis. Final vaccine structures were prepared by attaching azide and alkyne functional groups using click chemistry. The same methods were applied for the preparation of a library of control vaccine structures.In vitro uptake studies performed on macrophage (F4/80 + ) and dendritic (CD11c + ) cells showed significant uptake and/or binding for vaccine constructs containing mannose and lipid, and also for the lipopeptide vaccine construct without mannose when compared to the controls (containing no lipid, no mannose and no mannose or lipid). Further, in vitro mannan competition assays demonstrated that uptake of the mannosylated and lipidated vaccine constructs was MR mediated. To address the specificity of receptor uptake, surface plasmon resonance (SPR) was performed usingBiacore technology which confirmed a high affinity of the mannosylated and lipidated vaccine constructs towards the human recombinant MR in vitro when compared with vaccine constructs without mannose. These studies also confirmed that both mannose and lipid moieties play significant II roles in receptor-mediated uptake on APCs, potentially faci...

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The Mannose Receptor Mediates the Uptake of Diverse Native Allergens by Dendritic Cells and Determines Allergen-Induced T Cell Polarization through Modulation of IDO Activity

Cited by 162 publications

References 52 publications

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice

What makes an allergen?

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

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