# Presentation: 376442

## Murine Helicobacters: Models for Gastrointestinal Disease, or Confounders for in vivo Research?

**James G. Fox**
**Division of Comparative Medicine****MIT, Cambridge MA, USA**

## Helicobacter-Associated Hepatitis and Hepatocellular

**Neoplasms in Control A/JCr Male Mice**

**Fox *****et al***** 1994**
**Ward *****et al***** 1994**

**Number**

**May-July 1989 (n=47)**

**December 1992 (n=12)**

**12**
**(100%)**

**11**
**(92%)**

**1**
**(2%)**

**0**

## H. hepaticus in A/J mouse liver and colon

***H. hepaticus***** in A/J mouse liver and colon**

## Chronic hepatitis in A/JCr mice infected with Helicobacter hepaticus 

**Chronic hepatitis in A/JCr mice infected with *****Helicobacter hepaticus***** **

**Perivascular and periportal inflammation**
**Multifocal parenchymal necrosis**
**Bile duct and oval cell hyperplasia**
**Can progress to hepatic neoplasia**

## Characterization of the Response to Helicobacter hepaticus Infection in Recombinant Inbred Strains of Mice

**Characterization of the Response to *****Helicobacter hepaticus***** Infection in Recombinant Inbred Strains of Mice**

**Ihrig *****et al*****, Am J Path 1999**

## Characterization of the Response to Helicobacter hepaticus Infection in Recombinant Inbred Strains of Mice

**Characterization of the Response to *****Helicobacter hepaticus***** Infection in Recombinant Inbred Strains of Mice**

**Ihrig *****et al*****, Am J Path 1999**

## Listing of Nine NTP Studies with Helicobacter-associated Inflammatory Liver Lesions in Control B6C3F1 Male Mice

|  | Liver tumor incidence (%) |  | Nonneoplastic liver lesion incidence |  |
| --- | --- | --- | --- | --- |
|  | Males | Females | Males | Females |
| AZT 5000 (Interferon) | 72 | 48 | 76 | 4 |
| Sodium xylenesulfonate | 92 | 56 | 78 | 4 |
| Cobalt sulfate | 80 | 40 | 72 | 8 |
| AZT 500 (Interferon) | 48 | 40 | 66 | 0 |
| Chloroprene | 86 | 40 | 54 | 0 |
| Theophylline | 68 | 60 | 32 | 0 |
| Interferon | 62 | 69 | 22 | 4 |
| Triethanolamine | 62 | 46 | 20 | 0 |
| AZT alone | 72 | 54 | 16 | 2 |
| Average | 71 | 50 | 48 | 2 |

**Listing of Nine NTP Studies with Helicobacter-associated Inflammatory Liver Lesions in Control B6C3F1 Male Mice**

**Modified from NTP Report, 1996**

## H. hepaticus acts as a tumor promoter

**strain susceptibility**
**long term inflammatory state with increased reactive oxygen species prior to tumor formation**
**increased hepatocyte proliferation**
**lack of mutations in *****ras***** and *****p53***** genes**
**negative Ames assay and**
***H. hepaticus***** promotion of tumors by hepatocarcinogens **

## Slide 9

| Genotype | Background | PCR | Culture |
| --- | --- | --- | --- |
| nu/nu | NCr (outbred) | ND | + |
| nu/nu | Balb/C | + | + |
| nu/nu | C3H | ND | + |
| SCID | C.B-17TM | + | + |
| P53-/- | C57BL/6 | +* | + |
| TCR  -/- | C57BL/6 | ND | + |
| U-PA -/- | C57BL/6 | + | + |
| C3H/HeJBir** |  | + | + |

## Helicobacter hepaticus infection induces

***Helicobacter hepaticus***** infection induces**
**severe chronic hyperplastic typhlocolitis **
**in CD45RB****hi ****reconstituted *****scid***** mice**

## Helicobacter hepaticus and H. bilis associated IBD in Mice

| Genetic status of mice | Type of Defect |
| --- | --- |
| CD45RBhigh-reconstituted scids | Reconstitution with naïve CD4+T cell |
| TCR defined flora | Abnormal T cell receptors |
| Scid ICR defined flora | Lack T and B cell |
| IL-10 -/- | Knockout |
| RAG-2 -/- | Lack T and B cell |
| IL-7-/- / RAG-2-/- | Double Knockout |
| A/JCr | Normal |
| Swiss Webster gnotobiotic | Normal |
| p50 -/- p65 +/- | Double Knockout |
| mdr1a -/- | Lack P-glycoprotein |

***Helicobacter hepaticus***** and *****H. bilis***** associated IBD in Mice**