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Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy.

ABSTRACT: While sublingual immunotherapy (SLIT) is known as an allergen-specific treatment for type-1 allergies, how it controls allergic pathogenesis remains unclear. Here, we show the prerequisite role of conventional dendritic cells in submandibular lymph nodes (ManLNs) in the effectiveness of SLIT for the treatment of allergic disorders in mice. Deficiency of conventional dendritic cells or CD4⁺Foxp3⁺ regulatory T (T_reg) cells abrogates the protective effect of SLIT against allergic disorders. Furthermore, sublingual antigenic application primarily induces antigen-specific CD4⁺Foxp3⁺ T_reg cells in draining ManLNs, in which it is severely impaired in the absence of cDCs. In ManLNs, migratory CD11b⁺ cDCs are superior to other conventional dendritic cell subsets for the generation of antigen-specific CD4⁺Foxp3⁺ T_reg cells, which is reflected by their dominancy in the tolerogenic features to favor this program. Thus, ManLNs are privileged sites in triggering mucosal tolerance mediating protect effect of SLIT on allergic disorders that requires a tolerogenesis of migratory CD11b⁺ conventional dendritic cells.

SUBMITTER: Miyanaga N

PROVIDER: S-EPMC7721894 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy.

Miyanaga Noriaki N Takagi Hideaki H Uto Tomofumi T Fukaya Tomohiro T Nasu Junta J Fukui Takehito T Nishikawa Yotaro Y Sparwasser Tim T Choijookhuu Narantsog N Hishikawa Yoshitaka Y Nakamura Takeshi T Tono Tetsuya T Sato Katsuaki K

Communications biology 20201207 1

While sublingual immunotherapy (SLIT) is known as an allergen-specific treatment for type-1 allergies, how it controls allergic pathogenesis remains unclear. Here, we show the prerequisite role of conventional dendritic cells in submandibular lymph nodes (ManLNs) in the effectiveness of SLIT for the treatment of allergic disorders in mice. Deficiency of conventional dendritic cells or CD4+Foxp3+ regulatory T (Treg) cells abrogates the protective effect of SLIT ag ...[more]

PMID: 33288832

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Project description:BackgroundOral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown.ObjectiveWe sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow's milk (CM) allergy.MethodsWe randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG(4) levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels.ResultsThirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG(4) levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group.ConclusionOIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.

Dataset Information

Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy.

Publications

Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy.

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