Targeting the allergen to oral dendritic cells with mucoadhesive chitosan particles enhances tolerance induction.
BACKGROUND
Sublingual immunotherapy (SLIT) efficacy could be improved by formulations facilitating allergen contact with the oral mucosa and uptake by antigen-presenting cells (APCs).


METHODS
Two types of chitosan microparticles, differing in size and surface charge, were tested in vitro for their capacity to improve antigen uptake and presentation by murine bone marrow-derived dendritic cells (BMDCs) or purified oral APCs. T-cell priming in cervical lymph nodes (LNs) was assessed by intravenous transfer of carboxyfluorescein diacetate succinimidyl ester-labelled ovalbumin (OVA)-specific CD4+ T cells and flow cytometry analysis. Ovalbumin-sensitized BALB/c mice were treated sublingually with soluble or chitosan-formulated OVA twice a week for 2 months. Airway hyperresponsiveness (AHR), lung inflammation and T-cell responses in cervical and mediastinal LNs were assessed by whole-body plethysmography, lung histology and Cytometric Bead Array technology, respectively.


RESULTS
Only a mucoadhesive (i.e. highly positively charged) and microparticulate form of chitosan enhances OVA uptake, processing and presentation by murine BMDCs and oral APCs. Targeting OVA to dendritic cells with this formulation increases specific T-cell proliferation and IFN-gamma/IL-10 secretion in vitro, as well as T-cell priming in cervical LNs in vivo. Sublingual administration of such chitosan-formulated OVA particles enhances tolerance induction in mice with established asthma, with a dramatic reduction of both AHR, lung inflammation, eosinophil numbers in bronchoalveolar lavages, as well as antigen-specific Th2 responses in mediastinal LNs.


CONCLUSIONS
Mucoadhesive chitosan microparticles represent a valid formulation for sublingual allergy vaccines.
Saint-Lu
N
N
Research and Development, Stallergènes SA, Antony, France.
Tourdot
S
S
Razafindratsita
A
A
Mascarell
L
L
Berjont
N
N
Chabre
H
H
Louise
A
A
Van Overtvelt
L
L
Moingeon
P
P
D000286:Administration, Sublingual; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D048271:Chitosan / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003888:Desensitization, Immunologic / Q000379:methods*; D005260:Female; D006967:Hypersensitivity / Q000628:therapy*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009061:Mouth Mucosa / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D002614:Chelating Agents; D016753:Interleukin-10; D007371:Interferon-gamma; D010047:Ovalbumin; D048271:Chitosan