Th1-mediated immunity against Helicobacter pylori can compensate for lack of Th17 cells and can protect mice in the absence of immunization.

Hua Ding,Jinghua Xu,Brandon M Zagorski,John G Nedrud,Guanghui Li,Thomas G Blanchard,Steven J Czinn,Jessica Shiu

doi:10.1371/journal.pone.0069384

Abstract

Helicobacter pylori (H. pylori) infection can be significantly reduced by immunization in mice. Th17 cells play an essential role in the protective immune response. Th1 immunity has also been demonstrated to play a role in the protective immune response and can compensate in the absence of IL-17. To further address the potential of Th1 immunity, we investigated the efficacy of immunization in mice deficient in IL-23p19, a cytokine that promotes Th17 cell development. We also examined the course of Helicobacter infection in unimmunized mice treated with Th1 promoting cytokine IL-12. C57BL/6, IL-12 p35 KO, and IL-23 p19 KO mice were immunized and challenged with H. pylori. Protective immunity was evaluated by CFU determination and QPCR on gastric biopsies. Gastric and splenic IL-17 and IFNγ levels were determined by PCR or by ELISA. Balb/c mice were infected with H. felis and treated with IL-12 therapy and the resulting gastric bacterial load and inflammatory response were assessed by histologic evaluation. Vaccine induced reductions in bacterial load that were comparable to wild type mice were observed in both IL-12 p35 and IL-23 p19 KO mice. In the absence of IL-23 p19, IL-17 levels remained low but IFNγ levels increased significantly in both immunized challenged and unimmunized/challenged mice. Additionally, treatment of H. felis-infected Balb/c mice with IL-12 resulted in increased gastric inflammation and the eradication of bacteria in most mice. These data suggest that Th1 immunity can compensate for the lack of IL-23 mediated Th17 responses, and that protective Th1 immunity can be induced in the absence of immunization through cytokine therapy of the infected host.

Highlights

The association of gastric Helicobacter pylori (H. pylori) infection with peptic ulcer disease [1] and gastric cancer[2,3,4], combined with a world wide prevalence of infection of over 50%, has prompted many laboratories and companies to pursue development of a vaccine[5,6]
We demonstrate that deletions in either the p35 or p19 subunits that result in IL-12 and IL-23 deficiency respectively, may compromise the protective immune response but that bacterial loads remain significantly reduced
The present study demonstrates that vaccine-induced protective immunity against H. pylori can be achieved in hosts deficient in p19 IL-23

Summary

Introduction

The association of gastric Helicobacter pylori (H. pylori) infection with peptic ulcer disease [1] and gastric cancer[2,3,4], combined with a world wide prevalence of infection of over 50%, has prompted many laboratories and companies to pursue development of a vaccine[5,6] Such a vaccine would have great utility in areas of the world where the incidence of gastric cancer remains high[7]. The majority of prototype H. pylori vaccine work has been performed in murine models These models have been instrumental in identifying potential antigens, delivery routes, and adjuvants[6]. The mouse model continues to be used to develop improved adjuvants that might be applied in mucosal vaccination strategies in humans, and to identify the protective immune responses that might be enhanced by vaccine design to achieve improved efficacy in the clinic

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Results

Conclusion