Oral macrophage-like cells play a key role in tolerance induction following sublingual immunotherapy of asthmatic mice

Abstract

Sublingual allergen-specific immunotherapy (SLIT) is a safe and efficacious treatment for type 1 respiratory allergies. Herein, we investigated the key subset(s) of antigen-presenting cells (APCs) involved in antigen/allergen capture and tolerance induction during SLIT. Following sublingual administration, fluorochrome-labeled ovalbumin (OVA) is predominantly captured by oral CD11b⁺CD11c⁻ cells that migrate to cervical lymph nodes (CLNs) and present the antigen to naive CD4⁺ T cells. Conditional depletion with diphtheria toxin of CD11b⁺, but not CD11c⁺ cells, in oral tissues impairs CD4⁺ T-cell priming in CLNs. In mice with established asthma to OVA, specific targeting of the antigen to oral CD11b⁺ cells using the adenylate cyclase vector system reduces airway hyperresponsiveness (AHR), eosinophil recruitment in bronchoalveolar lavages (BALs), and specific Th2 responses in CLNs and lungs. Oral CD11b⁺CD11c⁻ cells resemble tolerogenic macrophages found in the lamina propria (LP) of the small intestine in that they express the mannose receptor CD206, as well as class-2 retinaldehyde dehydrogenase (RALDH2), and they support the differentiation of interferon-γ/interleukin-10 (IFNγ/IL-10)-producing Foxp3⁺ CD4⁺ regulatory T cells. Thus, among the various APC subsets present in oral tissues of mice, macrophage-like cells play a key role in tolerance induction following SLIT.

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

“…As such an induction has been reported to be dependent on allergen uptake by CD11b + cells present on the sublingual mucosa,20, 21 we were prompted to assess whether PM‐allergoids were better captured by these cells. For this purpose, fluorescent‐labeled allergen preparations were incubated with CD45 + cells isolated from the sublingual mucosa as described in Materials and Methods.…”

“…Previously, we have shown that the enhanced uptake of PM‐allergoids by human monocyte‐derived DCs is mediated by different C‐type lectin receptors binding mannose residues, such as CD206 (mannose receptor) and CD209 (DC‐SIGN) 16. 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.…”

Enhanced efficacy of sublingual immunotherapy by liposome-mediated delivery of allergen

“…10,38 Likewise, DCs (plasmacytoid, myeloid, and oral Langerhans cells) and macrophage like cells have been suggested in mice. 10,39 Immature DCs residing in mucosal tissue are highly efficient in probing the tissue environment and internalize nanocarriers such as liposomes by phagocytosis or micropinocytosis. 40,41 The internalization efficiency is dependent on particle size.…”

Adjuvants for allergy vaccines

“…Similarly, the adenylate cyclase protein from Bordetella pertussis fused to OVA enhanced tolerance induction via the sublingual route in mice with OVA-induced asthma, following capture by CD11b + tolerogenic myeloid DCs and macrophages. 68,69 As of today, none of those vector systems have been tested in humans in the context of mucosal allergy vaccines, although they raised the interest of the vaccine industry. [70][71][72] Noteworthy, maltodextrin-based mucoadhesive nanoparticles have been used to formulate an experimental flu vaccine, with evidence for the induction of strong mucosal IgA responses when administered intranasally to healthy volonteers.…”