Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

Uchida, Kazushige; Okazaki, Kazuichi; Nishi, Tatsushi; Uose, Suguru; Nakase, Hiroshi; Ohana, Masaya; Matsushima, Yumi; Omori, Katsuyuki; Chiba, Tsutomu

doi:10.1038/labinvest.3780435

Cited by 109 publications

(75 citation statements)

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“…by immunization with self-antigens, injection of pathogens [35] or via adoptive transfer of autoreactive cells or T regs [36][37][38]. However, such models can be highly variable.…”

Section: Discussionmentioning

confidence: 99%

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Seleznik¹,

Reding²,

Romrig

et al. 2012

Gastroenterology

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BACKGROUND AIMS:: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to development of AIP and new therapeutic strategies. METHODS:: We used quantitative PCR, immunohistochemical and ELISA analyses to measure expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing LT and specifically in acinar cells ( Ela1-LTab mice). RESULTS:: mRNA levels of lymphotoxin (LT) and were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines ( CXCL13, CCL19, CCL21, CCL1 and BAFF) was increased in pancreatic and serum samples from patients. Upregulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LT (Ela1-LT) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LT did not cause autoimmunity in mice without lymphocytes(Ela1-LTab/Rag1(-/-)); moreover lack of pro-inflammatory monocytes (Ela1-LTab/Ccr2-/-) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as anti-pancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS:: Overexpression of LT specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LT R ligands might be used to treat patients with AIP.

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“…by immunization with self-antigens, injection of pathogens [35] or via adoptive transfer of autoreactive cells or T regs [36][37][38]. However, such models can be highly variable.…”

Section: Discussionmentioning

confidence: 99%

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Seleznik¹,

Reding²,

Romrig

et al. 2012

Gastroenterology

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“…The data regarding the immunogenicity of CA-II and LF stand in contrast to a previous report showing that immunization with either of these two enzymes in thymectomized mice leads to pancreatitis. 16 The pathogenicity of immunization with amylase was not tested in Uchida and colleague's 16 groundbreaking work so it is not known if amylase can be used to induce pancreatitis in immunologically crippled animals. It is known that thymectomy greatly increases the rate and sensitivity to autoantigens 17 and as a result, both our work and possibly the work of Uchida and colleagues 16 point to a T cell etiology of AIP.…”

Section: Discussionmentioning

confidence: 99%

“…16 The pathogenicity of immunization with amylase was not tested in Uchida and colleague's 16 groundbreaking work so it is not known if amylase can be used to induce pancreatitis in immunologically crippled animals. It is known that thymectomy greatly increases the rate and sensitivity to autoantigens 17 and as a result, both our work and possibly the work of Uchida and colleagues 16 point to a T cell etiology of AIP. Thus it appears that in immunologically normal animals LF and CA-II are unable to induce EAP, whereas amylase can serve as a sufficient antigen.…”

Section: Discussionmentioning

confidence: 99%

An Experimental Model of Autoimmune Pancreatitis in the Rat

Davidson

Longnecker

Hickey

2005

The American Journal of Pathology

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“…This means complement activation through IgG1-triggering classical pathway is more likely to be involved in the pathogenesis. Uchida et al [90] skillfully created a model mimicking AIP. They used a well-established mouse model of autoimmune gastritis which is created by removal of thymus at 3 days after birth.…”

Section: Mechanismmentioning

confidence: 99%

Autoimmune pancreatitis in Japan: overview and perspective

Shimosegawa

Kanno

2009

J Gastroenterol

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Since the rediscovery and definition of autoimmune pancreatitis (AIP) by Yoshida et al. in 1995, the disease has been attracting attention because of its unique clinical features and practical issues. This disease shows very impressive imaging findings, serological changes, and characteristic histopathology. It occurs most commonly in elderly males with painless jaundice or mild abdominal pain; resemblance in imaging findings between AIP and pancreatobiliary cancers poses an important practical issue of differentiation. With increasing recognition of AIP and accumulation of cases, another important feature of this disease has been revealed, i.e

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Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

Cited by 109 publications

References 50 publications

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

An Experimental Model of Autoimmune Pancreatitis in the Rat

Autoimmune pancreatitis in Japan: overview and perspective

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