Helicobacter pylori infection and immunity. Protection after vaccination and regulation of inflammation in a mouse model

Abstract

Helicobacter pylori infection is an important cause of chronic active gastritis and peptic ulcer disease and a risk factor for the development of gastric cancer. An attractive strategy in the control of H. pylori infection is the development of a safe and effective therapeutic vaccine. Using a mouse model of H. pylori infection, we have studied the ability of different vaccine preparations to induce protective immunity against an existing H. pylori infection including also the problem whether induction of protective immunity by vaccination would lead to or aggravate gastritis in the infected mice. We report that both formalin-inactivated H. pylori bacteria and lysate antigens are effective as vaccines against a primary H. pylori SS1 infection and also against a subsequent reinfection. However, when using formalin-inactivated bacteria but not lysate antigens as a vaccine, serotype specificity in host protection against H. pylori infection was seen, relating to whether the vaccine and the infecting strains expressed the same or different Lewis (Le) antigens on their surface LPS. Thus, in designing a vaccine using inactivated bacteria, a mixture of strains expressing the prominent H. pylori Le antigens, together with cross protective lysate antigens could be required. Significant post-immunization gastritis was seen in mice that were protected after vaccination with either the lysate antigens or inactivated bacteria but not unimmunized or unprotected mice. Importantly, however, post immunization gastritis in the mice resolved three weeks after eradication of the H. pylori bacteria by antibiotic treatment. In an attempt to study the modulation of the immune responses to H. pylori infection two potent adjuvants, cholera toxin (CT) and CpG oligodeoxynucleotides (ODN), were used. We report here that intragastric co-administration of CT together with the H. pylori SS1 infection to mice resulted in strong protection against reinfection without causing any post-immunization gastritis. This was in sharp contrast to immunization with lysate antigens which resulted in protection after reinfection, but at the cost of severe post-immunization gastritis. In further studies using CpG ODN we saw that intragastric administration alone induced local production of chemokines in the gastric mucosa and also resulted in significant reduction in bacterial loads in the stomach of H. pylori infected mice; the protection correlated with both local gastric inflammation and chemokine production in the stomach. Finally, the role of immunoregulatory CD4+CD25+ T cells (Treg) in H. pylori induced gastritis was studied. Transfer of T cells depleted of Treg to athymic (nu/nu) mice and subsequent infection with H. pylori SS1 resulted in an earlier onset and increased severity of gastritis compared to nu/nu mice transferred with T cells containing Treg. In addition an enhanced activation of H. pylori specific IFN-g producing CD4+ T cells was seen in mice lacking Treg, compared to nu/nu mice transferred with T cells containing Treg.Our results suggest that therapeutic immunization against H.pylori infection using whole cell vaccines or lysate antigens can induce protective immunity suppressing the extent of infection but at the cost of significant but self-healing post-immunization gastritis. In the efforts to design a protective vaccine against H. pylori infection for humans we propose that a combined immunization and eradication strategy could work to counteract the risk of harmful effects of post-immunization gastritis while still ensuring the induction of a memory immune response against H. pylori antigens to protect against a subsequent reinfection.