Adjuvants et formulations de l’immunothérapie spécifique par voie sublinguale

Abstract

Sublingual immunotherapy (SLIT) is a non-invasive and efficacious treatment for type I respiratory allergies. To identify candidate adjuvants and galenic formulations capable of inducing tolerance by the sublingual route, an initial screening was carried out using in vitro cocultures of human monocyte-derived dendritic cells and naïve CD4⁺ T cells. Selected molecules were subsequently tested in a murine asthma model of sublingual immunotherapy in BALB/c mice sensitized to ovalbumin. In this model, we evaluated bronchial hyperreactivity (measured by whole-body plethysmography), pulmonary inflammation (evaluated histologically), and type 2 humoral and cellular immune responses monitored by Elisa and Elispot techniques in mice sensitized with either soluble or with adjuvant-formulated ovalbumin. Four categories of adjuvant known to increase IL-10 +/− IFNγ production by naïve CD4⁺ T cells (Treg/Th1) were found to enhance SLIT efficacy in vivo in these mice. These adjuvants were: vitamin D3/dexamethasone, Lactobacillus plantarum, the TLR2 agonist Pam3CSK4, and the TLR4 synthetic ligand OM-294-BA-MP. In addition, sublingual administration of ovalbumin combined with mucoadhesive maize-derived maltodextrin increased sublingual tolerance induction by targeting oral dendritic cells and ovalbumin-specific T cells in cervical and submaxillary lymph nodes. In conclusion, better understanding of specific immune responses to allergen at the level of the sublingual mucosa may lead to the development of new sublingual vaccines. In the future, such vaccines would incorporate Th1/Treg adjuvants, as well as mucoadhesive galenic formulations that target dendritic cells in the sublingual mucosa.