Induction of mucosal immune responses against Helicobacter pylori infection after sublingual and intragastric route of immunization

• Published in: Immunology 2017-02, Vol.150 (2), p.172-183
• Main Authors: Sjökvist Ottsjö, Louise, Jeverstam, Frida, Yrlid, Linda, Wenzel, Alexander U., Walduck, Anna K., Raghavan, Sukanya
• Format: Article
• Language: English
• Subjects: adjuvant; Adjuvants, Immunologic - administration & dosage; Administration, Sublingual; Animals; antibodies; Antigens; Antigens, Bacterial - immunology; Bacterial Toxins - administration & dosage; Bacterial Vaccines - immunology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Cholera Toxin - administration & dosage; cholera-toxin; cytokines; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Enterotoxins - administration & dosage; Escherichia coli Proteins - administration & dosage; Female; Gene expression; Helicobacter Infections - immunology; Helicobacter pylori - immunology; Immunity, Mucosal; Immunization; Immunologi; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; in-vivo; Infections; Inflammation Mediators - metabolism; Intubation, Gastrointestinal; Lymphatic system; Lymphocyte Activation; Mice; Mice, Inbred C57BL; migration; mucosa; Original; peyers-patches; T cell receptors; T cells; Tumor necrosis factor-TNF; vaccination; vaccine-induced protection; vibrio-cholerae
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12676

Summary There is a current lack of effective mucosal vaccines against major gastroenteric pathogens and particularly against Helicobacter pylori, which causes a chronic infection that can lead to peptic ulcers and gastric cancer in a subpopulation of infected individuals. Mucosal CD4+ T‐cell responses have been shown to be essential for vaccine‐induced protection against H. pylori infection. The current study addresses the influence of the adjuvant and site of mucosal immunization on early CD4+ T‐cell priming to H. pylori antigens. The vaccine formulation consisted of H. pylori lysate antigens and mucosal adjuvants, cholera toxin (CT) or a detoxified double‐mutant heat‐labile enterotoxin from Escherichia coli (dmLT), which were administered by either the sublingual or intragastric route. We report that in vitro, adjuvants CT and dmLT induce up‐regulation of pro‐inflammatory gene expression in purified dendritic cells and enhance the H. pylori‐specific CD4+ T‐cell response including interleukin‐17A (IL‐17A), interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) secretion. In vivo, sublingual immunization led to an increased frequency of IL‐17A+, IFN‐γ+ and TNF‐α+ secreting CD4+ T cells in the cervical lymph nodes compared with in the mesenteric lymph nodes after intragastric immunization. Subsequently, IL‐17A+ cells were visualized in the stomach of sublingually immunized and challenged mice. In summary, our results suggest that addition of an adjuvant to the vaccine clearly activated dendritic cells, which in turn, enhanced CD4+ T‐cell cytokines IL‐17A, IFN‐γ and TNF‐α responses, particularly in the cervical lymph nodes after sublingual vaccination. The influence of the route of mucosal immunization and type of adjuvant on the induction of Helicobacter pylori‐specific protective CD4+ T‐cell responses is not known. We could show in mice that activation of dendritic cells by adjuvants such as the cholera toxin and the detoxified heat labile enterotoxin from Escherichia coli enhanced the H. pylori antigen‐specific secretion of interleukin‐17A, interferon‐γ and tumour necrosis factor‐α by CD4+ T cells, particularly in the cervical lymph nodes after sublingual vaccination but not in the mesenteric lymph nodes after intragastric vaccination. We believe that the data presented in this study will aid in making choices regarding the optimal design of a vaccine and route of administration for protective immune responses against H. pylori infection in humans.