Inhibition of ADP ribosylation prevents and cures helicobacter-induced gastric preneoplasia.
Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium Helicobacter pylori. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing Helicobacter-specific T-cell priming and T(H)1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell-driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-gamma production of mesenteric lymph node T cells ex vivo. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-gamma, interleukin 2, and the interleukin 2 receptor alpha chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and T(H)1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of Helicobacter-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell-driven chronic inflammatory conditions and autoimmune pathologies.
Toller
Isabella M
IM
Institute of Molecular Cancer Research and Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Zürich, Switzerland.
Altmeyer
Matthias
M
Kohler
Esther
E
Hottiger
Michael O
MO
Müller
Anne
A
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000818:Animals; D005757:Gastritis, Atrophic / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000188:drug therapy* / Q000276:immunology; D016480:Helicobacter pylori / Q000254:growth & development*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D007376:Interleukin-2; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000244:Adenosine Diphosphate; D007371:Interferon-gamma