An Experimental Model of Autoimmune Pancreatitis in the Rat

Davidson, Todd S.; Longnecker, Daniel S.; Hickey, William F.

doi:10.1016/s0002-9440(10)62294-8

Cited by 41 publications

(25 citation statements)

References 16 publications

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“…The course of AIP progression is consistent with the notion of amylase as a key autoantigen for disease initiation and dissemination. These results are consistent with those describing amylase as a potential autoantigen for AIP in rats (41). However, in our model, amylase is not the only autoantigen involved in the development of AIP since there are clearly other specificities observed both by immunofluorescence and IB analyses, consistent with AIP being a chronic disease characterized by changes in the autoimmune repertoire over time (59).…”

Section: Discussionsupporting

confidence: 93%

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

Meagher¹,

Tang

Fife³

et al. 2008

The Journal of Immunology

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Autoimmune pancreatitis (AIP) is a heterogeneous autoimmune disease in humans characterized by a progressive lymphocytic and plasmacytic infiltrate in the exocrine pancreas. In this study, we report that regulatory T cell-deficient NOD.CD28KO mice spontaneously develop AIP that closely resembles the human disease. NOD mouse AIP was associated with severe periductal and parenchymal inflammation of the exocrine pancreas by CD4+ T cells, CD8+ T cells, and B cells. Spleen CD4+ T cells were found to be both necessary and sufficient for the development of AIP. Autoantibodies and autoreactive T cells from affected mice recognized a ∼50-kDa protein identified as pancreatic amylase. Importantly, administration of tolerogenic amylase-coupled fixed spleen cells significantly ameliorated disease severity, suggesting that this protein functions as a key autoantigen. The establishment and characterization of this spontaneous pancreatic amylase-specific AIP in regulatory T cell-deficient NOD.CD28KO mice provides an excellent model for the study of disease pathogenesis and development of new therapies for human autoimmune pancreatitis.

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Section: Discussionsupporting

confidence: 93%

“…In addition, another study showed that amylasebut not carbonic anhydrase II-nor lactoferrin-sensitized T cell lines were sufficient to transfer AIP into immunocompetent rat strains (41). Together with our immunofluorescent and IB results (Figs.…”

Section: Direct Demonstration That Amylase Is a Specific Autoantigen supporting

confidence: 84%

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

Meagher¹,

Tang

Fife³

et al. 2008

The Journal of Immunology

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“…Furthermore, the adoptive transfer of amylase-specific CD4 ϩ T-cells to rats was able to confer pancreatitis, whereas the transfer experiment with lactoferrin-specific or CAII-specific CD4 ϩ T-cells failed to induce experimental pancreatitis (23). Our findings of a high prevalence of autoantibody against AMY-2A in human AIP and the results from the adoptive transfer experiment of amylasespecific CD4…”

Section: Discussionsupporting

confidence: 48%

Amylase α-2A Autoantibodies

et al. 2009

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OBJECTIVE-The pathogenesis of autoimmune pancreatitis (AIP) and fulminant type 1 diabetes remains unclear, although it is known that immune-mediated processes severely compromise the endocrine and exocrine functions in both diseases. RESEARCH DESIGN AND METHODS-We have screened aTriplEx2 human pancreas cDNA library with serum from a patient with AIP and obtained positive clones. Sequence analysis revealed that 7 of 10 clones were identical to human amylase ␣-2A. Using a recombinant COOH-terminal amylase ␣-2A protein, we developed an enzyme-linked immunosorbent assay system to detect autoantibodies against human amylase ␣-2A.RESULTS-All 15 serum samples from patients with AIP recognized the recombinant protein, whereas sera from 25 patients with chronic alcoholic pancreatitis and sera from 25 patients with a pancreas tumor did not. Interestingly, 88% (15/17) of patients with fulminant type 1 diabetes were positive for an autoantibody against amylase ␣-2A. These antibodies were detected in 21% of patients with acute-onset type 1 diabetes (9 of 42) and 6% of type 2 diabetic patients (4 of 67).CONCLUSIONS-These results suggest that an autoantibody against amylase ␣-2A is a novel diagnostic marker for both AIP and fulminant type 1 diabetes and that, clinically and immunologically, AIP and fulminant type 1 diabetes are closely related. Diabetes 58:732-737, 2009 R ecently, autoimmune pancreatitis (AIP), a unique form of chronic pancreatitis, has been reported as a discrete disease entity (1). It is characterized by 1) irregular narrowing of the main pancreatic duct and swelling of the pancreas, both of which are due to abundant lymphoplasmacytic inflammation to the exocrine pancreas (2); 2) the increased serum level of IgG and IgG4; 3) positive autoantibodies such as lactoferrin autoantibody or carbonic anhydrase II (CAII) autoantibody (3,4); and 4) a high prevalence of diabetes with complications (5).We recently reported that a high proportion of pancreatic islets and exocrine pancreatic tissues were infiltrated by CD4 ϩ or CD8 ϩ T-cells in the inflammatory process, which might induce diabetes in AIP (6). In addition, treatment with prednisolone improved insulin secretion and glycemic control in AIP patients (5). These data support the concept that autoimmune mechanism(s) plays a pivotal role in the destruction of the endocrine and exocrine pancreas in AIP patients with diabetes.Clinically, the most common initial symptom of AIP is jaundice, but in some patients, no symptoms or only mild symptoms, frequently without acute attacks of pancreatitis, may be present (7). It is difficult to distinguish AIP from other types of chronic pancreatitis or cancer of the pancreatic head (8). In such cases, detection of autoantibodies is useful for diagnosing AIP, but a proportion of patients with AIP are negative for autoantibodies against lactoferrin and CAII (3,4).We encountered an AIP patient whose serum IgG and IgG4 levels were 3,498 and 2,430 mg/dl, respectively. It has been reported that median levels (5th and 95th percentile...

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“…Previous studies have shown that CD8 ϩ and CD4 ϩ T cells abundantly infiltrate the pancreatic tissue (11 ), and carbonic anhydrase II might be one of the target antigens (12 ). Activated CD4 ϩ T cells specific for pancreatic amylase can induce pancreatitis in the rat that is similar to human AIP (13 ). Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), which is expressed on activated CD8 ϩ and CD4…”

mentioning

confidence: 99%