Vaccine-Induced Immunity Against Helicobacter pylori in the Absence of IL-17A

Abstract

Helicobacter pylori (H. pylori) is a gram negative bacterium that can cause diseases such as peptic ulcers and gastric cancer. IL-17A, a proinflammatory cytokine that can induce the production of CXC chemokines for neutrophil recruitment, has recently been shown to be elevated in both H. pylori-infected patients and mice. Furthermore, studies in mouse models of vaccination have reported levels significantly increased over infected, unimmunized mice and blocking of IL-17A during the challenge phase in immunized mice reduces protective immunity. Because many aspects of immunity had redundant or compensatory mechanisms, we investigated whether mice could be protectively immunized when IL-17A function is absent during the entire immune response using IL-17A and IL-17A receptor knockout (KO) mice immunized against H. pylori. Gastric biopsies were harvested from naïve, unimmunized/challenged, and immunized/challenged wild type (WT) and KO mice and analyzed for inflammation, neutrophil, and bacterial levels. Groups of IL-17A KO mice were also treated with anti-IFNγ or control antibodies. Surprisingly, all groups of immunized KO mice reduced their bacterial loads comparably to WT mice. The gastric neutrophil counts did not vary significantly between IL-17A KO and WT mice, whereas IL-17RA KO mice had on average a four-fold decrease compared to WT. Additionally, we performed an immunization study with CXCR2 KO mice and observed significant gastric neutrophils and reduction in bacterial load. These data suggest that there are compensatory mechanisms for protection against H. pylori and for neutrophil recruitment in the absence of an IL-17A-CXC chemokine pathway.

Suppression of IL-8 production in gastric epithelial cells by MUC1 mucin and peroxisome proliferator-associated receptor-γ

“…pylori stomach infection and histopathology. An in vivo H. pylori gastric infection model system has been previously described (13,14,17,18). In this system, colonization efficiency is routinely Ͼ90% as determined by the percent of infected animals from which H. pylori can be recovered, either as viable bacteria and by testing for bacterial urease, oxidase, and catalase activities to confirm their identity as H. pylori, or by real-time RT-PCR for bacterial gene sequences (e.g., urease C).…”

Th1-Mediated Immunity against Helicobacter pylori Can Compensate for Lack of Th17 Cells and Can Protect Mice in the Absence of Immunization

“…This inflammation is dependent on CD4 + T cells[12], and many studies demonstrate that Th1, Th17, or both Th1 and Th17 immunity are required[10], [13], [14], [15], [16], [17], [18], [19]. Initial studies using mice deficient in the IL-12 family p40 subunit showed a lack of vaccine induced protection[18], [19].…”

A Double Mutant Heat-Labile Toxin from Escherichia coli, LT(R192G/L211A), Is an Effective Mucosal Adjuvant for Vaccination against Helicobacter pylori Infection

“…We now report that sublingual immunization with dmLT and H. pylori lysate antigens strongly increases IFN-␥ and IL-17A gene expression in the stomachs of mice and also the production of these cytokines by MLN and spleen cells after in vitro stimulation with H. pylori antigens. Effective induction of IL-17 is desirable when designing a vaccine against H. pylori infection, since one of the functions of IL-17 is to recruit neutrophils, which have been shown to be essential in reducing the bacterial loads in the stomachs of vaccinated mice (28), although DeLyria et al have reported that in mice immunized with H. pylori lysate antigens and CT, neutrophils can be recruited to the stomach after challenge independent of IL-17A (29). However, IL-17 has multiple roles, and we believe that its main function in H. pylori infection is to promote bacterial clearance by possibly recruiting bactericidal neutrophils and also to stimulate local IgA antibody formation (30).…”