Human Embryonic Gastric Xenografts in Nude Mice: a New Model of Helicobacter pylori Infection

Abstract

In vitro or animal models have been used to investigate the pathogenesis of Helicobacter pylori infection. However, extrapolation to humans of results obtained with these heterologous models remains difficult. We have developed a new model for the study of H. pylori infection that uses human entire embryonic stomachs engrafted in nude mice. At 80 days after implantation, 22 of these xenografts, which exhibited a mature gastric epithelium, were inoculated with 107 to 108 CFU of eitherH. pylori LB1, a freshly isolated H. pyloristrain (n = 12), or H. pylori ATCC 49503 (n = 10). After 12-week examination, H. pylori LB1 persistently colonized the antrum of all inoculated grafts, as assessed by culture (mucus and mucosa), immunohistochemistry (mucosa), and a rapid urease test (mucus). H. pylori ATCC 49503, either before or after in vivo passage, permitted only a transient 2-week colonization in one of the five inoculated grafts in both groups. Colonization was always associated with an increase of gastric juice pH. A mild neutrophil infiltration of the gastric mucosa was noted solely in infected grafts. Transmission electron microscopy showed adherence of H. pylori organisms to epithelial cell surface. In six animals, intracytoplasmic location of this bacterium was observed in the antrum or the fundus. These results allow us to propose this model as a new ex vivo model for the study of specificH. pylori-gastric cell interactions.

Gastric Penetration of Amoxicillin in a Human Helicobacter pylori -Infected Xenograft Model

“…This model has previously been described in detail (19). Briefly, human embryonic stomachs (gestational age, 6 to 8 weeks) were obtained after legal abortion.…”

“…This permitted us to ensure that the gastric juice was acid, since the pH ranged from 1.5 to 2 for all grafts studied. Five randomly assigned grafts were inoculated, through the gastric catheter, two times at 3-day intervals with 0.6 ml of a bacterial suspension (approximately 10 8 organisms/ml in tryptose soy broth [Oxoid, Basingstoke, United Kingdom]) of H. pylori LB1, which was originally isolated from a patient with duodenal ulcer and severe gastritis (19). Three months after inoculation, each animal was anesthetized as described above.…”

“…The severe combined immunodeficient mice, in which human fetal thymic and liver tissues have been implanted, was recently proposed as a model for determination of the in vivo effectiveness of different therapeutic agents on immunodeficiency virus infection (28). We have previously developed a new model of H. pylori infection in nude mice using human gastric xenografts which exhibit differentiated human gastric epithelium (19). The aim of this work was to investigate the usefulness of this model for the study of amoxicillin penetration into the infected human stomach after parenteral administration.…”

Breaking the species barrier: use of SCID mouse-human chimeras for the study of human infectious diseases

“…Whole‐organ transplants are not limited to the human intestinal xenografts. Pancreas, stomach and liver have been successfully engrafted into SCID mice (Lozniewski et al ., 1999a; Si et al ., 2001). McCune et al .…”

“…A number of animal models for H. pylori exist that have led to important findings about the mechanisms of H. pylori colonization, the identity of H. pylori virulence factors and the role of inflammation and immune responses in disease (Nedrud et al ., 2002). Lozniewski et al . (1999a) have pioneered studies of H. pylori infection in human stomach, using nude mice that were engrafted with human fetal gastric tissue.…”