Gastroenterology

Gastroenterology

Volume 129, Issue 1, July 2005, Pages 142-155
Gastroenterology

Basic-alimentary tract
Mast Cells Are Critical Mediators of Vaccine-Induced Helicobacter Clearance in the Mouse Model

Presented in part at the annual meeting of the American Gastroenterology Association 2004, at the 12th International Congress of Immunology 2004 and published in abstract form (Velin D, Bachmann D, Bouzourene H, Michetti P. Mast cells are key players in the immune mechanisms leading to Helicobacter clearance after vaccine therapy. Gastroenterology 2004;126A107).
https://doi.org/10.1053/j.gastro.2005.04.010Get rights and content

Background & Aims: Despite the proven ability of immunization to prevent Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. Methods: We explored the cellular events associated with Helicobacter clearance from the stomach following vaccination by flow cytometry analysis and histological and molecular studies. Results: Kinetic studies showed that the infection is undetectable in vaccinated mice at day 5 postbacterial challenge. Flow cytometry analysis showed that the percentages of mast cells (CD3CD117+) increased in the lymphoid cells isolated from the stomach at day 4 postchallenge in urease + cholera toxin (CT)-vaccinated mice in comparison with mice administered with CT alone (9.4% ± 4.4% and 3.1% ± 1%, respectively, for vaccinated and CT administered, n = 5; P < .01). Quantitative PCR analysis showed an increased messenger RNA (mRNA) expression of the mast cell proteases 1 and 2 at day 5 postchallenge in the stomach of vaccinated mice. In contrast to wild-type mice, mast cell-deficient mice (W/Wv mice) were not protected from H felis colonization after vaccination. Indeed only 1 out of 12 vaccinated W/Wv mice showed a negative urease test. Remarkably, vaccinated W/Wv mice reconstituted with cultured bone marrow-derived mast cells recovered the ability to clear the infection after vaccination (8 out of 10 mast cell-reconstituted mice showed negative urease tests [P < .006 as compared with wild-type mice]). Conclusions: These experiments show that mast cells are, unexpectedly, critical mediators of anti-Helicobacter vaccination.

Section snippets

Mice

WB/ReJ-KitW/+ and C57BL/6J-KitWv/+ mice were purchased from the Jackson Laboratory (Bar Harbor, ME) and mated in our SPF animal facility. We used either male or female 6- to 8-week-old W/Wv and WBB6F1 +/+ mice. Female Balb/c mice (6 to 8 weeks old) were purchased from Harlan, Horst, The Netherlands. This study was approved by the State of Vaud Veterinary Office (authorization No. 836.6).

Immunization, In Vivo CD4+ Cells Depletion, and Mastocytosis Induction

Mice were immunized intranasally 4 times at 1-week intervals with 30 μg recombinant H pylori urease (kindly

Kinetics Studies of Vaccination-Mediated Clearance of Helicobacter

We first studied the kinetics of H felis clearance in wild-type mice vaccinated intranasally with urease + CT. At day 4 postchallenge, infection, as defined by positive urease tests on gastric mucosa samples, was detected in 4 out of 5 urease + CT-vaccinated mice (Figure 1A). At day 5 postchallenge, only 2 out of 10 vaccinated mice showed positive urease tests, whereas 10 out of 10 control mice vaccinated with CT alone were positive. Gastric histologic analysis confirmed the presence of H felis

Discussion

Vaccination against H pylori is an important goal in the prevention of gastroduodenal diseases, including ulcers and gastric malignancies. Despite the proven ability of vaccination to prevent or reduce Helicobacter infection in animal models, the precise mechanisms of protection have remained obscure. Mucosal and systemic immunizations with Helicobacter extracts or purified recombinant proteins generate antigen-specific serum and salivary and intestinal antibody responses as well as cellular

References (57)

  • J.M. Wastling et al.

    Histochemical and ultrastructural modification of mucosal mast cell granules in parasitized mice lacking the beta-chymase, mouse mast cell protease-1

    Am J Pathol

    (1998)
  • T. Jippo et al.

    Tissue-dependent alteration of protease expression phenotype in murine peritoneal mast cells that were genetically labeled with green fluorescent protein

    Am J Pathol

    (2001)
  • E.N. Geissler et al.

    The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene

    Cell

    (1988)
  • F. Feger et al.

    The role of mast cells in host defense and their subversion by bacterial pathogens

    Trends Immunol

    (2002)
  • V.L. Ott et al.

    Activating and inhibitory signaling in mast cellsnew opportunities for therapeutic intervention?

    J Allergy Clin Immunol

    (2000)
  • S. Mecheri et al.

    Unravelling the mast cell dilemmaculprit or victim of its generosity?

    Immunol Today

    (1997)
  • Y.A. Mekori et al.

    Mast cell-T cell interactions

    J Allergy Clin Immunol

    (1999)
  • S. Nakajima et al.

    Mast cell involvement in gastritis with or without Helicobacter pylori infection

    Gastroenterology

    (1997)
  • F.C. Icatlo et al.

    Acid-dependent adherence of Helicobacter pylori urease to diverse polysaccharides

    Gastroenterology

    (2000)
  • G. Klausz et al.

    Effects of Helicobacter pylori infection on gastric inflammation and local cytokine production in histamine-deficient (histidine decarboxylase knock-out) mice

    Immunol Lett

    (2004)
  • M.J. Blaser et al.

    Parasitism by the slow bacterium Helicobacter pylori leads to altered gastric homeostatis and neoplasia

    J Clin Invest

    (1994)
  • S.J. Czinn et al.

    Immunopathology of Helicobacter pylori infection and disease

    Springer Semin Immunopathol

    (1997)
  • S. Suerbaum et al.

    Helicobacter pylori infection

    N Engl J Med

    (2002)
  • H. Kleanthous et al.

    Rectal and intranasal immunizations with recombinant urease induce distinct local and serum immune responses in mice and protect against Helicobacter pylori infection

    Infect Immun

    (1998)
  • A. Dubois et al.

    Immunization against natural Helicobacter pylori infection in nonhuman primates

    Infect Immun

    (1998)
  • G. Del Giudice et al.

    The design of vaccines against Helicobacter pylori and their development

    Annu Rev Immunol

    (2001)
  • J. Pappo et al.

    Helicobacter pylori infection in immunized mice lacking major histocompatibility complex class I and class II functions

    Infect Immun

    (1999)
  • T.H. Ermak et al.

    Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses

    J Exp Med

    (1998)
  • Cited by (77)

    • Gastric eosinophils are detrimental for Helicobacter pylori vaccine efficacy

      2021, Vaccine
      Citation Excerpt :

      The control group received 200 μl of BHI. Quantification of Hp colony forming units (CFU) was used to assess infection status [24]. CFU were determined immediately after stomach collection.

    • The Role of Mast Cells in Bacterial Infection

      2016, American Journal of Pathology
      Citation Excerpt :

      Hence, the latter findings provide further support for a role of MCs in regulating adaptive immune responses against bacteria.29 Consistent with this, Shelburne et al25 showed that MCs promoted the antibody response to E. coli, and it has been demonstrated that MCs play a critical role in anti-Helicobacter vaccination.39 Several studies have indicated that MCs can act directly on bacteria, although it should be recognized that there is only limited in vivo evidence to support this notion.

    • Mast Cells, Basophils and Mucosal Immunity

      2015, Mucosal Immunology: Fourth Edition
    View all citing articles on Scopus

    Supported by the Swiss National Foundation (grant 3100-068243 to P.M.).

    View full text