Vaccine-induced protection against Helicobacter pylori in mice lacking both antibodies and interleukin-4

Abstract

To test the hypothesis that a Th2 response to Helicobacter pylori is necessary for protection and to address the possibility that humoral and Th2 cellular responses may compensate for each other, we generated mice deficient in both interleukin-4 (IL-4) and antibodies. The immunized double-knockout mice were protected from H. pylori challenge, as were the parental strains and wild-type C57BL/6 mice. Neutralization of IL-4 in B-cell-deficient mice did not prevent protection. Immunized IL-5-deficient mice were also protected. Thus, IL-4 and IL-5 are not essential for protection.

FIG. 1.

Mice genetically lacking IL-4 and/or antibodies were protected by intranasal immunization and had H. pylori-induced gastritis similar to that of WT mice at 4 weeks after challenge. (A) Quantitative culture results (log CFU per gram of stomach) are shown as the geometric mean ± standard error for each group. Each I/C group had a >2-log decrease in mean colonization compared to its respective U/C group. ‡, all unchallenged mice H. pylori negative. (B) Gastric inflammation was graded in the worst ×10 field on a scale of 0 to 5. The I/C and U/C groups of each strain were not different, but both challenged groups had significantly more inflammation than the respective U/NC group. *, P < 0.0001; †, P < 0.001; §, P < 0.01; ¶, P < 0.05.

FIG. 2.

Depletion of IL-4 during immunization or challenge does not block protective immunity in B-cell-deficient mice. Open symbols show bacterial colonization in individual mice, and solid squares indicate the geometric mean ± standard error. The threshold for protection (dashed line) is a 2-log decrease from the mean of the U/C mice. Control or anti-IL-4 antibodies (Ab) were administered during immunization (immun.) or challenge periods. Colonization in the three groups of immunized mice is significantly less than that in unimmunized mice, but the three immunized groups are not different from one another. *, P < 0.005.

FIG. 3.

IL-5 KO mice were protected 4 weeks after challenge. (A) Colonization by H. pylori is expressed as the geometric mean ± standard error. Both immunized groups showed a >2-log decrease from their respective U/C group. *, P ≤ 0.0005. (B) Gastritis was not statistically different in the I/C and U/C groups. Untreated IL-5 KO mice had significantly lower scores than I/C and U/C groups of both strains, and untreated WT mice had less inflammation than both I/C groups. †, P < 0.006; §, P ≤ 0.02.