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WO1999035907A2 - Modele - Google Patents

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Publication number
WO1999035907A2
WO1999035907A2 PCT/IB1999/000217 IB9900217W WO9935907A2 WO 1999035907 A2 WO1999035907 A2 WO 1999035907A2 IB 9900217 W IB9900217 W IB 9900217W WO 9935907 A2 WO9935907 A2 WO 9935907A2
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WO
WIPO (PCT)
Prior art keywords
animal
helicobacter pylori
pylori
infection
dogs
Prior art date
Application number
PCT/IB1999/000217
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English (en)
Other versions
WO1999035907A3 (fr
Inventor
Giuseppe Del Giudice
Rino Rappuoli
Original Assignee
Chiron S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9801000.2A external-priority patent/GB9801000D0/en
Priority claimed from GBGB9809398.2A external-priority patent/GB9809398D0/en
Priority claimed from GBGB9820976.0A external-priority patent/GB9820976D0/en
Application filed by Chiron S.P.A. filed Critical Chiron S.P.A.
Priority to NZ500160A priority Critical patent/NZ500160A/en
Priority to JP53695899A priority patent/JP2001523116A/ja
Priority to AU20709/99A priority patent/AU2070999A/en
Priority to CA002283401A priority patent/CA2283401A1/fr
Priority to EP99901086A priority patent/EP0967858A2/fr
Publication of WO1999035907A2 publication Critical patent/WO1999035907A2/fr
Publication of WO1999035907A3 publication Critical patent/WO1999035907A3/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates

Definitions

  • the present invention relates to an animal infected with Helicobacter pylori (H. pylori) capable of inducing acute symptoms and of maintaining a chronic infection of H. pylori, useful as a model for H. pylori infection.
  • the model is especially useful for the development of vaccines and chemotherapeutics against H. pylori and diagnostics.
  • H. pylori was isolated in 1982 by B. Marshall and J. Warren using microaerophilic conditions that had been developed to grow Campylobacter jejuni.
  • H. pylori bacteria are S-shaped, gram negative bacilli 2-3.5 ⁇ m in length and 0.5-1 ⁇ m in width (4).
  • H. pylori is responsible for the most common infection in the world. In developing countries 80% of the population is infected by the bacterium at the age of 20, while in developed countries H. pylori infection increases with age from ⁇ 20% in 30-year old people to >50% in 60-year olds (2, 4) The infection is transmitted by either the oro-fecal or the oro-oral route (4). Infection occurs during the first years of life and persists forever. Once established, the infection is chronic, possibly permanent. Risk factors for infection are crowding, poor hygiene and host-specific genetic factors.
  • H. pylori chronic infection of the human gastroduodenal mucosae by H. pylori is frequently associated with chronic gastritis, peptic ulcer, and increases the risk of occurrence of gastric malignancies such as adenocarcinoma and low grade B cell lymphoma (4, 43, 44). Most of the infections remain asymptomatic, whereas symptomatic, severe diseases correlate epidemiologically with the infection by a subset of H. pylori strains, called Type I (5-7, 13, 55).
  • H. pylori Colonization of the mucosa of the stomach by H. pylori is today recognized as the major cause of acute and chronic gastroduodenal pathologies in humans (4, 6).
  • the recognition of the infectious nature of the illness is having a major impact in the treatment of the disease that is shifting from the treatment of symptoms by anti-H2 blockers to the eradication of the bacterial infection by antibiotic regimen.
  • Vaccine development requires understanding of a number of critical steps that are not yet fully studied. These are:
  • H. pylori freshly isolated from human gastroduodenal biopsies, have been adapted to persistently colonize the gastric mucosa of xenobiotic mice (37). This model has proven particularly useful to assess the feasibility of either preventive (36-38, 46) or therapeutic (18) vaccination, as well as for the in vivo screening of anti-H. pylori antimicrobials (33), and for studying the pathogenesis of infection (48).
  • mice have to be sacrificed; the pathological changes induced by the chronic infection and/or the effect of therapeutic or immunizing regimens cannot, therefore, be followed up in the same individual animal.
  • the present invention describes for the first time an animal model which can reproduce symptoms which have been clearly associated with the acute phases of infection with H. pylori (39, 40, 41 , 49) in humans.
  • the present application is based on the discovery that H. pylori can persistently colonize the gastric mucosa of conventional xenobiotic dogs, and that this colonization causes acute symptoms, histopathological lesions and elicits specific immune responses.
  • a non- human, non-murine animal infected with Helicobacter pylori which exhibits one or more acute symptoms of Helicobacter pylori infection.
  • the Helicobacter pylori establishes chronic persistent infection in the infected animal.
  • acute symptoms includes chronic gastritis, peptic ulcer, and increased risk of occurrence of gastric malignancies such as adenocarcinoma and low-grade B-cell lymphoma.
  • the animal may be any non-human, non-murine animal capable of sustaining an infection with Helicobacter pylori and exhibiting one or more acute symptoms of Helicobacter pylori infection.
  • the animal is a larger animal (i.e. larger than a rat, mouse or guinea pig), suitably one adapted to laboratory use, such as a cat, dog, sheep, goat, pig, monkey, or horse.
  • Larger animal models are useful because the progression of the experimental infection can be followed in a single animal. This has the advantage of reducing the error in following disease progression associated with the analysis of a number of different, smaller animals, such as mice.
  • Using dogs as animal models for human disease also has the advantage that the physiology of a dog is similar to that of a human. The possibility of stable infection is to be contrasted with infections which exhibit the acute symptoms of Helicobacter pylori infection.
  • the animal is xenobiotic dog.
  • the dog is a beagle.
  • a method for infecting an animal according to the first aspect of the invention with Helicobacter pylori comprising the steps of:
  • the administration of Helicobacter pylori is repeated at intervals after the initial infection.
  • the administration of Helicobacter pylori is repeated 3 times every other day after the initial infection for one week.
  • stomach acid of the animal is neutralised.
  • the isolate of Helicobacter pylori is passaged several times in vivo prior to administration.
  • the process further comprises of the step of:
  • the isolate of Helicobacter pylori in step (a) is isolated from a non- human animal.
  • the non-human animal is a mouse.
  • the animal model contemplated by the present invention has the advantage that the cost of experiments is reduced. For example, many experimental mice would be required to attempt to follow the disease progression of experimental H. pylori infection compared to just one animal, for example, a dog.
  • the pH of a dog's stomach is as low as a human's stomach, whereas the pH of a mouse's stomach is higher.
  • FIG. 1 Histopathology and endoscopic findings in infected dogs.
  • PI gastric mucosa at 1 week post-infection
  • E A round hyperemic, superficial erosion of antral gastric mucosa observed by endoscopy at 4 weeks PI.
  • H & E stain of antral mucosa at 4 weeks PI showing vacuolar degeneration (arrows) of the epithelium (original magnification 400x).
  • FIG. 3 Detection of H. pylori in gastric biopsies by PCR.
  • H. pylori DNA amplification of the cagA sequence showing a PCR product of 298-bp in gastric biopsies of dogs collected at 4 and 12 weeks PI but not in gastric samples collected before infection.
  • Figure 4 Antibody responses during infection.
  • Figure 4A shows the serum IgG antibody response to a H. pylori bacterial lysate and to two purified H. pylori antigens, CagA and VacA. Each curve individuates single dogs.
  • Figure 4B shows the IgA and IgG antibody response to H. pylori bacterial lysate in the saliva. Each curve individuates single dogs. Results are expressed as the optical densities at 405 nm in salivary samples diluted 1 :20.
  • Figure 5 Endoscopic findings in protected and infected dogs. Shows endoscopic examination of the antral region of protected dogs (Figure 5A) and control (infected) dogs ( Figure 5B) 42 days after challenge with H. pylori.
  • H. pylori Type I strain persistently colonizes the stomach of xenobiotic beagle dogs, causes acute symptoms and gastric pathology, and elicits specific immune responses.
  • lymphoid structures may represent the consequence of an active and persistent stimulation of the immune system at the local mucosal level, with recruitment in situ of specific T-cells (27). It has been reported that in some individuals such lymphoid structures in the gastric mucosa may precede the development of low grade B-cell lymphoma (44).
  • H. pylori was identified in the gastric biopsies by immunohistochemistry, TEM, urease test, and PCR. Furthermore, it was also possible to culture the bacteria from the gastric biopsies and the rectal swabs. This clearly shows that the evolution of the pathology in this model is constantly associated with the presence of H. pylori. It should be stressed that viable H. pylori was recoverable at any time of observation, even at 24 weeks after infection. This finding is in agreement with the recovery of H. mustelae in the stools of experimentally infected ferrets (15).
  • H. pylori induced an early detectable antibody response to different antigens, including CagA and VacA, both in serum and saliva, which persisted during the entire period of follow up.
  • H. pylori cell lysate i.e. H. pylori cell lysate
  • Control dogs #2 and #3 had diarrhea during the first week after the last challenge. Control dog #2 also had vomiting. There were no symptoms of H. pylori infection in the i.m. group.
  • Urease test on gastric (antral) biopsy and on gastric lavage was positive in the control group, and negative in the i.m. group as shown in Table 2 below, even 24 h later. These data were also confirmed at day 42 post-challenge. Table 2
  • Serum IgG titers Serum IgA titers to: Serum IgA titers to
  • ⁇ Titers are expressed as the last serum dilution giving an optical density equal or higher than 0.2. Titers ⁇ 100 (IgG) and ⁇ 20 (IgA) are considered as negative.
  • H. pylori strain SPM326s, a streptomycin-resistant derivative of the mouse-adapted H. pylori Type I (CagA+/VacA+) strain SPM326 (37), was grown as previously described (37) and used for the infection of dogs. Animals and experimental design. Three 4-6 months-old xenobiotic beagle dogs, one male and two females (Morini s.a.s., S. Polo D'Enza, Italy), were selected on the basis of the absence of detectable serum IgG against H. pylori in Western blot (WB) analysis using total bacterial lysate as antigen (see below).
  • WB Western blot
  • the three dogs selected were housed in standard conditions and maintained on a diet of dry food (MIL, Morini s.a.s.) and tap water ad libitum. Upon arrival in our animal facilities, an additional WB analysis on sera confirmed their H. pylori status. The dogs were housed in individual cages and allowed to adapt for a month to the new environment. During the month of adaptation, two tests were carried out on fecal samples to assess the presence of intestinal parasites or common enteric pathogenic bacteria.
  • the dogs were then challenged 3 times every other day over a one-week period with the mouse-adapted H. pylori SPM326s strain as follows: 24 h before each challenge the dogs were fasted. 2 h before bacteria inoculation, dogs received 10 mg/kg of cimetidine intramuscularly (i.m.) (Tagamet® 200; Smith Kline & French, USA).
  • the dogs were anesthetized with a mixture of 40 ⁇ g/kg of medetomidine chloridrate (Domitor®; Centralvet- Vetem s.p.a., Milano, Italy) and 5 mg/kg of ketamine (Ketavet®, Gellini, Latina, Italy) intravenously (i.v.); then a gastric lavage was performed with 100 ml of 0.2M NaHCO 3 sterile solution followed by oral challenge with 3 ml of a freshly prepared suspension of 10 9 CFUs in sterile saline of the H. pylori strain SPM326s, grown under microaerobic conditions (see below), prepared immediately before the inoculation procedure.
  • Domitor® Centralvet- Vetem s.p.a., Milano, Italy
  • ketamine Keramine
  • anesthetic antagonist atipamezole (Antisedan®; Centralvet-Vetem s.p.a., Milano, Italy) was administered and then dogs were again treated with cimetidine and fed after 2 h.
  • Blood samples, salivary samples, and oropharyngeal and rectal swabs were collected under sterile conditions immediately before the challenge and at 1 , 2,
  • gastric endoscopies were performed using a 4.9-mm-diameter Pentax pediatric bronchoscope (Pentax Technologies, Zaventem, Belgium).
  • Pre-challenge gastric biopsies were taken during the endoscopies using flexible pinch-biopsy forceps at the antrum, corpus, fundus, and cardias for urease testing and for microbiological, PCR, histopathological and immunohistochemical analyses. Before each endoscopy the whole instrument and the flexible forceps were soaked in 4% glutaraldehyde for 45 minutes and then rinsed in sterile saline.
  • Rapid urease test Antral biopsies were incubated for up to 24 h in 1 ml of a 10% urea solution in distilled water added with two drops of a 1 % phenol red solution (Sigma Chemical Co., St. Louis, MO, USA) in sodium phosphate buffer, pH 6.5. A positive test is indicated by change of color (from orange to dark pink) in the medium; the time necessary for the color change is recorded (Table 3). The time to positivity of this test has been shown to be proportional to the number of bacteria present at the biopsy site (22).
  • PCR Polymerase chain reaction
  • Oligonucleotides were synthesized on an Applied Biosystem synthesizer (Applied Biosystems Inc., Foster City, CA, USA) by the automated phosphoramidite coupling method and purified by standard protocols.
  • Applied Biosystems Inc. Foster City, CA, USA
  • PCR mixture contained 50 mM KCI, 10 mM Tris, 200 mM deoxynucleoside triphosphates, 30 pmol of each primer, 0.1 ⁇ g of bovine serum albumin, 2.5 U of Amplitaq (Perkin-Elmer, Norwalk, Connecticut, USA), and 80 ng of H. pylori chromosomal DNA. Amplifications were performed on a PCR system 9600 thermocycler (Perkin-Elmer) with the following cycling profiles: 94°C for 30 s, 65°C for 30 s, and 72°C for 30 s for 38 cycles and then extension at 72°C for 7 minutes.
  • H. pylori antibodies SDS-PAGE of H. pylori (strain SPM326s) and WB analysis of sera were performed according to previously published procedures (37). Briefly, dog sera were diluted 1 :200 and incubated for 2 h at room temperature. Then, horseradish peroxidase (HRP)-conjugated rabbit anti-dog IgG antibody (Nordic Immunological Laboratories, Tilburg, The Netherlands) was added at 1 :2,000 dilution for 2 h, and the reaction was developed using 4- ⁇ -chloronaphtol as substrate. Detection of antibody against H.
  • HRP horseradish peroxidase
  • pylori by ELISA was carried out on 96-well plates coated overnight at 4°C with SPM326s lysate (10 ⁇ g/well) or with purified native VacA or CagA (0.2 ⁇ g/well). Coated wells were blocked with PBS containing 5% non-fat milk. Twofold serial dilutions of the sera were incubated at 37°C for 2 h and then washed with PBS. Antigen specific IgG titers were determined using a 1 :4,000 dilution of HRP-conjugated rabbit anti-dog IgG polyclonal antibody for 2 h at 37°C.
  • Antigen bound antibodies were revealed by adding o-phenylenediamine dihydrochloride (Sigma) as a substrate.
  • o-phenylenediamine dihydrochloride Sigma
  • Similar assays were utilized by diluting salivary samples 1 :20 and utilizing alkaline phosphatase-conjugated goat anti-lgA or -IgG antibodies.
  • Antibody titers were determined as previously described (18).
  • FIG. 1 E Histological sections showed vacuolar degeneration, loss of the apical secreting portion of the cells, piknosis and rhexis of epithelial cell nuclei (Figs. 1 F, G and H).
  • foliicular gastritis with the characteristic 'bumpy' aspect of the gastric wall (Fig. 11), was easily detected by endoscopy in all three animals. Histological examination of gastric biopsies revealed the presence of small lymphoplasmacytic aggregates among the glands of the corpus and fundus; small lymphoid follicles (1.5-2 mm) appeared in the antrum (Fig. 1L). Associated with these follicles, degenerative processes in the epithelial cells, presence of scattered neutrophilic granulocytes, and an increase of exocytosis of mononuclear cells (Fig. 1 M) were observed.
  • H. pylori was identified in the biopsies immunohistochemically using H. py/or/ ' -specific monoclonal antibodies (Mabs). Figs. 1 K and J show H. pylori, stained with the C1G9 anti-VacA Mab, in the mucous layer of the antrum at 8 and 16 weeks PI, respectively. H. pylori was also observed by TEM in the lumen of antral glands, in close association with epithelial cell membranes (Fig. 2). Isolation and identification of H. pylori. The presence of H. pylori in the biopsies taken from the gastric mucosa of experimentally infected dogs was first assessed by the rapid urease test.
  • results of microbiological cultures are summarized in Table 3.
  • H. pylori was identified by culture, although at these time points the growth of bacteria from the selective culture plates was rather scanty. From the 8th week PI onward, the growth of H. pylori from all the gastric bioptic samples was more evident from all three dogs, and 100-500 H. pylori colonies were easily recovered from each biopsy (not shown). At later times (i.e. at 18 and 24 weeks PI) in two of the three dogs, the bacterium was easily isolated from body and antrum only, whereas a marked decrease in the growth efficiency was observed in biopsies taken from cardias and fundus.
  • H. pylori could also be cultured from rectal swabs of the three animals (Table 3). These microbiological findings were always confirmed by PCR performed on the bacterial colonies grown on the plates (not shown).
  • PCR was carried out on antral biopsy samples taken at time zero and at each endoscopic examination using ca ⁇ //4-specific primers. The presence of H. pylori was confirmed in all PI samples (Table 3).
  • Fig. 3 shows the PCR products obtained in antral gastric biopsies taken at 4 and 12 weeks PI.
  • H. pylori-specific IgG antibodies were already detectable two weeks after infection and persisted at high titer during the entire follow up of the study.
  • the three dogs mounted an antibody response against VacA and CagA, which also persisted for the entire study.
  • both IgG and IgA specific for H. pylori antigens appeared in the saliva of the three dogs.
  • the titers of these antibodies increased over time, reached their peaks between weeks 12 and 15 PI, and then declined, although they were still detectable 24 weeks after infection.
  • H. pylori strains SPM326s, a streptomycin-resistant derivative of the mouse-adapted H. pylori Type I (CagA+/VacA+) strain SPM326 (37), was grown as previously described (37) and used to challenge the dogs.
  • the CCUG strain of H. pylori is well known in the art.
  • H. pylori Challenge with infectious H. pylori.
  • the dogs were then challenged on days 49, 51 and 53 with the mouse-adapted H. pylori SPM326s strain as follows: 24 h before each challenge the dogs were fasted. 2 h before bacteria inoculation, dogs received 10 mg/kg of cimetidine i.m. (Tagamet® 200; Smith Kline & French, USA).
  • the dogs were anesthetized with a mixture of 40 ⁇ g/kg of medetomidine chloridrate (Domitor®; Centralvet- Vetem s.p.a., Milano, Italy) and 5 mg/kg of ketamine (Ketavet®, Gellini, Latina, Italy) intravenously (i.v.); then a gastric lavage was performed with 100 ml of 0.2 M NaHCO 3 sterile solution followed by oral challenge with 3 ml of a freshly prepared suspension of 10 9 CFUs in sterile saline of the H. pylori strain SPM326s, grown under microaerobic conditions (see below), prepared immediately before the inoculation procedure.
  • Domitor® Centralvet- Vetem s.p.a., Milano, Italy
  • ketamine Keramine
  • anesthetic antagonist atipamezole (Antisedan®; Centralvet-Vetem s.p.a., Milano, Italy) was administered and then dogs were again treated with cimetidine and fed after 2 h.
  • Rapid urease test Antral biopsies and liquid from gastric lavage were incubated for up to 24 h in 1 ml of a 10% urea solution in distilled water added with two drops of a 1 % phenol red solution (Sigma Chemical Co., St. Louis, MO, USA) in sodium phosphate buffer, pH 6.5. A positive test is indicated by change of color (from orange to dark pink) in the medium; the time necessary for the color change is recorded. At time 0, endoscopy was carried out on the six dogs and antral biopsies were taken for the urease test. In all six dogs, the urease test was negative at time 0.
  • the samples were fixed in 10% buffered formalin and embedded in paraffin.
  • H. pylori antibodies SDS-PAGE of H. pylori (strain SPM326s) and WB analysis of sera were performed according to previously published procedures (37). Briefly, dog sera were diluted 1 :200 and incubated for 2 h at room temperature. Then, horseradish peroxidase (HRP)-conjugated rabbit anti-dog IgG antibody (Nordic Immunological Laboratories, Tilburg, The Netherlands) was added at 1 :2,000 dilution for 2 h, and the reaction was developed using 4- ⁇ -chloronaphtol as substrate. Detection of antibody against H.
  • HRP horseradish peroxidase
  • pylori by ELISA was carried out on 96-well plates coated overnight at 4°C with the prepared CCUG strain lysate used for immunization (5 ⁇ g/well) or with purified native CagA or NAP (0.2 ⁇ g/well). Coated wells were blocked with PBS containing 5% non-fat milk. Twofold serial dilutions of the sera were incubated at 37°C for 2 h and then washed with PBS. Antigen specific IgG titers were determined using a 1 :4,000 dilution of HRP-conjugated goat anti-dog IgG antibody (Bethyl Laboratories, Inc., Montgomery, TX, USA) for 2 h at 37°C. Antigen bound antibodies were revealed by adding o-phenylenediamine dihydrochloride (Sigma) as a substrate. Antibody titers were determined as previously described (18). References
  • Helicobacter pylori Aliment. Pharmacol. Ther. 10 (Suppl. 1): 29-37. 11. Crabtree, J.E., P. Peichl, J.I. Wyatt, U. Stachl, and I.J. Lindley. 1993. Gastric interleukin-8 and IgA IL-8 autoantibodies in Helicobacter pylori infection. Scand. J. Immunol. 37: 65-70.
  • MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the Cag-A protein. Gastroenterology. 112:1482-1486.

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  • Life Sciences & Earth Sciences (AREA)
  • Environmental Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Zoology (AREA)
  • Animal Husbandry (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un modèle animal qui peut être infecté expérimentalement par Helicobacter pylori et qui présente les symptômes aigus d'une infection à Helicobacter pylori. On prépare ledit modèle en injectant à un animal, tel qu'un chien xénobiotique, une dose de bactéries antérieurement adaptées à la souris. L'invention concerne également l'utilisation d'un modèle animal pour le développement de vaccins, de médicaments chimiques et de méthodes diagnostiques.
PCT/IB1999/000217 1998-01-16 1999-01-15 Modele WO1999035907A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
NZ500160A NZ500160A (en) 1998-01-16 1999-01-15 Xenobiotic canine model of Helicobacter pylori infection
JP53695899A JP2001523116A (ja) 1998-01-16 1999-01-15 Ｈ．ｐｙｌｏｒｉ感染の生体異物動物モデル
AU20709/99A AU2070999A (en) 1998-01-16 1999-01-15 Xenobiotic animal model of H. Pylori infection
CA002283401A CA2283401A1 (fr) 1998-01-16 1999-01-15 Modele animal xenobiotique de l'infection h. pylori
EP99901086A EP0967858A2 (fr) 1998-01-16 1999-01-15 Modele

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GBGB9801000.2A GB9801000D0 (en) 1998-01-16 1998-01-16 Crystalline carbapenem intermediates and process for synthesis thereof
GB9801000.2 1998-01-16
GB9809398.2 1998-04-30
GBGB9809398.2A GB9809398D0 (en) 1998-04-30 1998-04-30 Immunization and treatment
GB9820976.0 1998-09-25
GBGB9820976.0A GB9820976D0 (en) 1998-09-25 1998-09-25 Immunization and treatment

Publications (2)

Publication Number Publication Date
WO1999035907A2 true WO1999035907A2 (fr) 1999-07-22
WO1999035907A3 WO1999035907A3 (fr) 1999-09-23

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EP (1) EP0967858A2 (fr)
JP (1) JP2001523116A (fr)
AU (1) AU2070999A (fr)
CA (1) CA2283401A1 (fr)
NZ (1) NZ500160A (fr)
WO (1) WO1999035907A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001011953A1 (fr) * 1999-08-19 2001-02-22 Board Of Regents, The University Of Texas System Modele animal grande echelle d'aspergillose pulmonaire invasive chez un hote immunodeprime

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116369278B (zh) * 2023-05-17 2024-09-20 上海溯源生物技术有限公司 一种幽门螺杆菌感染的动物模型构建方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3189795A (en) * 1994-09-28 1996-04-19 Biocine S.P.A. Mouse model for helicobacter pylori infection
EP0757888A4 (fr) * 1994-12-13 1997-11-26 Yoshitomi Pharmaceutical Gerbille de mongolie colonisee par helicobacter pylori, procede pour realiser cette colonisation, milieu pour la separation de helicobacter pylori et procede d'evaluation preliminaire de substances actives contre helicobacter pylori
SE9503309D0 (sv) * 1995-09-25 1995-09-25 Astra Ab Method to identify therapeutically active compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001011953A1 (fr) * 1999-08-19 2001-02-22 Board Of Regents, The University Of Texas System Modele animal grande echelle d'aspergillose pulmonaire invasive chez un hote immunodeprime

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WO1999035907A3 (fr) 1999-09-23
NZ500160A (en) 2002-03-01
EP0967858A2 (fr) 2000-01-05
JP2001523116A (ja) 2001-11-20
AU2070999A (en) 1999-08-02
CA2283401A1 (fr) 1999-07-22

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