The Wistar Bonn Kobori rat, a unique animal model for autoimmune pancreatitis with extrapancreatic exocrinopathy

Sakaguchi, Yutaku; Inaba, Muneo; Tsuda, Motoyuki; Quan, Gang; Omae, Mariko; Ando, Yugo; Uchida, Kazushige; Okazaki, Kazuichi; Ikehara, Susumu

doi:10.1111/j.1365-2249.2008.03588.x

Cited by 32 publications

(30 citation statements)

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“…In contrast to males, female rats of this strain do not show pancreatitis. Sakaguchi et al reported that female rats develop dacryoadenitis at 3 months of age, and that both male and female WBN/Kob rats develop sialoadenitis, thyroiditis, sclerotic cholangitis, and tubulointerstitial nephritis over 18 months of age [24]. These features were observed in autoimmune pancreatitis and autoimmune disease [24].…”

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confidence: 84%

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

Akimoto

Terada

Shimizu

2012

The Journal of Veterinary Medical Science

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ABSTRACT. We established the WBN/Kob-Lepr fa rat as a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr fa rats provide a model of non-insulin-dependent diabetes, although its onset is secondary to pancreatitis. In the present study, we compared histopathological observations of pancreatitis in each genotype of this rat, to examine its suitability as a model of pancreatitis. The histopathological findings of the pancreatitis revealed intense changes dependent on age, such as hemorrhage or hemosiderin deposition. The pancreatitis in homozygous (fa/fa) WBN/Kob-Lepr fa rats were more severe than those of WBN/ Kob rats. Pancreatitis is a common disorder of the exocrine the pancreas in dogs and cats. Clinical diagnosis of chronic pancreatitis is challenging because the disease is usually mild or subclinical, and its clinical signs are often the same as those of complicating or concurrent diseases. Pancreatitis is inflammation of the pancreas introduced by autodigestion and results in leakage of digestive enzymes. In rats and mice, experimental pancreatitis can be induced by ethanol feeding, [30] Original WBN/Kob rats were the spontaneous model of the pancreatitis [22]. Male WBN/Kob rats commonly develop chronic pancreatitis by the age of 3 months, while diabetes mellitus occurs at 9 months [10,18,19,28]. In contrast to males, female rats of this strain do not show pancreatitis.The leptin receptor fatty gene (Lepr fa ) is a recessive mutation that leads to leptin receptor deficiency, and homozygous animals (fa/fa) show obesity, hyperphagia, insulin resistance, hyperinsulinemia, and glucose intolerance [5,13,27,31]. The leptin receptor fatty gene accelerates pancreatitis and diabetes in WBN/Kob-Lepr fa rats. In the present study, we compared histopathological observations of pancreatitis in each genotype, to examine the suitability of using WBN/Kob-Lepr fa rats as a model of pancreatitis. Each genotype (fa/fa, +/fa, and +/+) of WBN/Kob-Lepr fa rats was produced by mating heterozygous (+/fa) males with heterozygous (+/fa) females. Genotyping of the fa mutation was performed according to the method described by Masuyama [15]. The animals were given a commercial diet (MF, Oriental Yeast Co. Tokyo, Japan) and tap water ad libitum, and were housed in an air-conditioned room (24  2C, 50~60% relative humidity, and lights on for 14 hr per day from 6:00 to 20:00). The number of animals in each group is detailed in Table 1. At 7, 9, 11, and 13 weeks of age, a blood sample was collected for each genotype (fa/fa, +/fa, and +/+), while blood glucose levels were measured with a portable glucose meter (Asensia Breeze) (Bayer-Sankyo). Rats were then sacrificed by ether anesthesia. The pancreas was removed, fixed overnight in Bouin's solution, and embedded in paraffin for histopathological analyses. Serial 4-m sections were cut and then stained with hematoxylin-eosin for histological examination. All sections were examined histopathologically and findings were graded from norm...

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confidence: 84%

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

Akimoto

Terada

Shimizu

2012

The Journal of Veterinary Medical Science

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“…[28][29][30][31] To date, several animal models of AIP have been reported. [31][32][33][34][35] In most models, the AIP-like disease is induced by the adoptive transfer of autoreactive cells and self-antigens such as CA-II and LF. Similarly, the adaptive transfer of E. coli-inoculated mice spleen cells to RAG2 À/À mice also reproduced AIP-like pancreatitis in the present study.…”

Section: Discussionmentioning

confidence: 99%

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Haruta

Yanagisawa

Kawamura

et al. 2010

Laboratory Investigation

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The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heatkilled Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.

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“…Our previous report demonstrated that WBN/Kob rats develop daxryoadenitis, sialoadenitis, thyroiditis, sclerotic cholangitis and tubulointerstitial nephritis, and is a useful animal model for AIP and Sjögren-like syndrome in humans. IBM-BMT has been shown to prevent these ADs in this animal model [12]. However, IBM-BMT has a long way to go before an effective standard regimen of AD therapy for patients has been developed.…”

Section: Aip Treated With Ibm-bmtmentioning

confidence: 90%

“…Allogenic Hematopoietic Stem Cell (HSC) transplantation has been shown to be a relatively successful treatment for experimental ADs, and there are a number of reports of Bone Marrow Transplantation (BMT) being used to treat ADs in various mice [3][4][5][6][7][8][9][10]. For example, the following were all resolved after BMT: Insulin-Dependent Diabetes Mellitus (IDDM), in which beta cells are destroyed by the immune system; Rheumatoid arthritis (RA), which primarily attacks the synovial joints; Systemic Lupus Erythematosus (SLE), which is a chronic auto-inflammatory disease of unknown etiology; Multiple Sclerosis (MS), which affects the brain and the central nervous system, and Autoimmune Pancreatitis (AIP), which produces pancreatic masses and ductal strictures [11,12]. ADs show abnormal autoimmune responses by auto-antibodies and T-cell responses to self-molecules in pathological conditions [13].…”

Section: Introductionmentioning

confidence: 99%

Autoimmune Disease Treatment with Stem Cell Transplantation

Li¹,

Ikehara²

2013

J Genet Syndr Gene Ther

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Autoimmune Diseases (ADs) are diseases in which the immune system mistakenly attacks and destroys selfmolecules due to a disruption of immunologic tolerance to auto-reactive immune cells. The goals of treatments for ADs are to 1) reduce symptoms, 2) control the autoimmune process and 3) maintain the body's ability to fight disease. Allogenic Hematopoietic Stem Cell (HSC) transplantation has been shown to be a relatively successful treatment for experimental ADs. Intra Bone Marrow-Bone Marrow Transplantation (IBM-BMT) has been proven to be a powerful strategy for allogeneic BMT due to the rapid hemopoietic recovery and the complete restoration of T cell functions even in donor-recipient combinations across MHC barriers. In this review, we summarize the ADs treatable with IBM-BMT.

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The Wistar Bonn Kobori rat, a unique animal model for autoimmune pancreatitis with extrapancreatic exocrinopathy

Cited by 32 publications

References 43 publications

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Autoimmune Disease Treatment with Stem Cell Transplantation

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