Spontaneous Development of a Pancreatic Exocrine Disease in CD28-Deficient NOD Mice

Meagher, Craig; Tang, Qizhi; Fife, Brian T.; Bour-Jordan, Hélène; Wu, Jenny Q.; Pardoux, Cécile; Bi, Mingying; Melli, Kristin; Bluestone, Jeffrey A.

doi:10.4049/jimmunol.180.12.7793

Cited by 45 publications

(31 citation statements)

References 69 publications

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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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“…Previous findings in this model have shown that this mouse develops profound T1D as well as autoimmune exocrine disease due to limited Treg numbers (16,17). Given the more rapid course of FT1D in humans and the proposed role of viral infection in disease pathogenesis, we examined the effect of administration of a mimic of dsRNA, polyinosinic-polycytidylic acid [poly(I:C)], which has been suggested to increase pathogenic T cells and Tregs in conventional NOD mice (18), to CD28 2/2 NOD mice.…”

mentioning

confidence: 86%

A Mimic of Viral Double-Stranded RNA Triggers Fulminant Type 1 Diabetes-like Syndrome in Regulatory T Cell-Deficient Autoimmune Diabetic Mouse

Tada

Shimada

Yamada

et al. 2011

The Journal of Immunology

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Human fulminant type 1 diabetes (FT1D) is an extremely aggressive disease. The delay of proper diagnosis results in high mortality. However, the pathophysiology of this disease remains unclear. We took advantage of CD28-deficient NOD (CD28−/− NOD) mice, which have limited numbers of regulatory T cells and develop aggressive autoimmune diabetes, to create a FT1D model that mimicked the disease in humans. Young CD28−/− NOD mice were injected with polyinosinic-polycytidylic acid to activate innate immunity in an effort to induce diabetes onset. In this model, innate immune cell activation precedes the onset of diabetes similar to ∼70% of FT1D patients. Eighty-three percent of CD28−/− NOD mice developed diabetes within 1–6 d after injection of polyinosinic-polycytidylic acid. Moreover, T cells infiltrated the pancreatic exocrine tissue and destroyed α cells, an observation characteristic of human FT1D. We conclude that an FT1D-like phenotype can be induced in the background of autoimmune diabetes by a mimic of viral dsRNA, and this model is useful for understanding human FT1D.

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“…Finally, antibodies anti-alfa-2-amylase have been recently described in a subgroup of patients affected by autoimmune pancreatitis presenting with fulminant diabetes [381], a form that is commonly considered 'non-autoimmune.' In these patients, the lymphocyte infiltrate affecting the exocrine component in autoimmune pancreatitis is extended to the islets [381] and may reveal shared immune-mediated mechanisms, as seem to be suggested in the NOD mouse [382].…”

Section: B Cells and Autoantibodiesmentioning

confidence: 99%

Immunology of β-Cell Destruction

Torre

Lernmark

2010

Advances in Experimental Medicine and Biology

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Spontaneous Development of a Pancreatic Exocrine Disease in CD28-Deficient NOD Mice

Cited by 45 publications

References 69 publications

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

A Mimic of Viral Double-Stranded RNA Triggers Fulminant Type 1 Diabetes-like Syndrome in Regulatory T Cell-Deficient Autoimmune Diabetic Mouse

Immunology of β-Cell Destruction

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