The regulatory roles of Th1 and Th2 cells in immune protection against Helicobacter infection are not clearly understood. In this study, we report that a primary H. pylori infection can be established in the absence of IL-12 or IFN-γ. However, IFN-γ, but not IL-12, was involved in the development of gastritis because IFN-γ−/− (GKO) mice exhibited significantly less inflammation as compared with IL-12−/− or wild-type (WT) mice. Both IL-12−/− and GKO mice failed to develop protection following oral immunization with H. pylori lysate and cholera toxin adjuvant. By contrast, Th2-deficient, IL-4−/−, and WT mice were equally well protected. Mucosal immunization in the presence of coadministered rIL-12 in WT mice increased Ag-specific IFN-γ-producing T cells by 5-fold and gave an additional 4-fold reduction in colonizing bacteria, confirming a key role of Th1 cells in protection. Importantly, only protected IL-4−/− and WT mice demonstrated substantial influx of CD4+ T cells in the gastric mucosa. The extent of inflammation in challenged IL-12−/− and GKO mice was much reduced compared with that in WT mice, indicating that IFN-γ/Th1 cells also play a major role in postimmunization gastritis. Of note, postimmunization gastritis in IL-4−/− mice was significantly milder than WT mice, despite a similar level of protection, indicating that immune protection is not directly linked to the degree of gastric inflammation. Only protected mice had T cells that produced high levels of IFN-γ to recall Ag, whereas both protected and unprotected mice produced high levels of IL-13. We conclude that IL-12 and Th1 responses are crucial for H. pylori-specific protective immunity.
Helicobacterfelis inoculated per os into germfree mice and their conventional non-germfree counterparts caused a persistent chronic gastritis of-1 year in duration. Mononuclear leukocytes were the predominant inflammatory cell throughout the study, although polymorphonuclear cell infiltrates were detected as well. Immunohistochemical analyses of gastric mucosa from H. felis-infected mice revealed the presence of mucosal B220+ cells coalescing into lymphoid follicles surrounded by aggregates of Thy-1.2+ T cells; CD4+, CD5+, and of T cells predominated in organized gastric mucosal and submucosal lymphoid tissue, and CD11b+ cells occurred frequently in the mucosa. Follicular B cells comprised immunoglobulin M' (IgM+) and IgA+ cells. Numerous IgA-producing B cells were present in the gastric glands, the lamina propria, and gastric epithelium. Infected animals developed anti-H. felis serum IgM antibody responses up to 8 weeks postinfection and significant levels of IgG anti-H. felis antibody in serum, which remained elevated throughout the 50-week course of the study.
The ability of oral immunization to interfere with the establishment of infection with Helicobacter felis was examined. Groups of Swiss Webster mice were immunized orally with 250 g of Helicobacter pylori recombinant urease (rUrease) and 10 g of cholera toxin (CT) adjuvant, 1 mg of H. felis sonicate antigens and CT, or phosphate-buffered saline (PBS) and CT. Oral immunization with rUrease resulted in markedly elevated serum immunoglobulin G (IgG), serum IgA, and intestinal IgA antibody responses. Challenge with live H. felis further stimulated the urease-specific intestinal IgA and serum IgG and IgA antibody levels in mice previously immunized with rUrease but activated primarily the serum IgG compartment of PBS-treated and H. felisimmunized mice. Intestinal IgA and serum IgG and IgA anti-urease antibody responses were highest in rUrease-immunized mice at the termination of the experiment. Mice immunized with rUrease were significantly protected (P Յ 0.0476) against infection when challenged with H. felis 2 or 6 weeks post-oral immunization in comparison with PBS-treated mice. Whereas H. felis-infected mice displayed multifocal gastric mucosal lymphoid follicles consisting of CD45R ؉ B cells surrounded by clusters of Thy1.2 ؉ T cells, gastric tissue from rUrease-immunized mice contained few CD45R ؉ B cells and infrequent mucosal follicles. These observations show that oral immunization with rUrease confers protection against H. felis infection and suggest that gastric tissue may function as an effector organ of the mucosal immune system which reflects the extent of local antigenic stimulation.
The role of major histocompatibility complex (MHC) class I- and class II-restricted functions in Helicobacter pyloriinfection and immunity upon oral immunization was examined in vivo. Experimental challenge with H. pylori SS1 resulted in significantly greater (P ≤ 0.025) colonization of MHC class I and class II mutant mice than C57BL/6 wild-type mice. Oral immunization with H. pylori whole-cell lysates and cholera toxin adjuvant significantly reduced the magnitude of H. pylori infection in C57BL/6 wild-type (P = 0.0083) and MHC class I knockout mice (P = 0.0048), but it had no effect on the H. pylori infection level in MHC class II-deficient mice. Analysis of the anti-H. pyloriantibody levels in serum showed a dominant serum immunoglobulin G1 (IgG1) response in immunized C57BL/6 wild-type and MHC class I mutant mice but no detectable serum IgG response in MHC class II knockout mice. Populations of T-cell-receptor (TCR) αβ+CD4+ CD54+ cells localized to gastric tissue of immunized C57BL/6 wild-type and MHC class I knockout mice, but TCRαβ+ CD8+ cells predominated in the gastric tissue of immunized MHC class II-deficient mice. These observations show that CD4+ T cells engaged after mucosal immunization may be important for the generation of a protective anti-H. pylori immune response and that CD4+CD8− and CD4− CD8+ T cells regulate the extent of H. pylori infection in vivo.
In this study, we demonstrate the role of M cells in uptake of poly(D-L-lactic-co-glycolic acid) (PLGA) microspheres and transport into rabbit Peyer's patches. Microspheres 1 to 10 microns in diameter composed of 50:50 lactic acid:glycolic acid were instilled into intestinal segments containing jejunal or ileal Peyer's patches, and uptake by M cells was examined by electron microscopy. PLGA microspheres visualized as electron-lucent, spherical particles were taken up by M cells by pseudopod-like extensions of the M cell apical membrane and translocated to the pocket region containing mononuclear leukocytes within 60 min. These results indicate that PLGA microspheres can be directed to M cell apical surfaces for delivery to immunocompetent cells in gut-associated lymphoid tissues.
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