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Spontaneous Development of a Pancreatic Exocrine Disease in CD28-Deficient NOD Mice¹

Craig Meagher^*, Qizhi Tang, Brian T. Fife^*, Helene Bour-Jordan^*, Jenny Wu^*, Cecile Pardoux^*, Mingying Bi^*, Kristin Melli and Jeffrey A. Bluestone^2,*

^* Diabetes Center and Department of Surgery, University of California, San Francisco, CA 94143

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI50834-02 (to J.B), P30 DK63720 (to J.B.), U19 AI056388 (to J.B.), a career development award 10-2006-799 (to B.T.F.), and Postdoctoral Research Fellowship 3-2004-316 (to C.M.) from the Juvenile Diabetes Research Foundation.

² Address correspondence and reprint requests to Dr. Jeffrey A. Bluestone, Diabetes Center, University of California, 513 Parnassus Avenue, Box 0540, San Francisco, CA 94143. E-mail address: jbluest{at}diabetes.ucsf.edu

³ Abbreviations used in this paper: AIP, autoimmune pancreatitis; Treg, regulatory cell; T1D, type 1 diabetes; BGL, blood glucose level; PDC, primary pancreatic ductal cell; ZG, zymogen granule; SI, stimulation index; PVDF, polyvinylidene difluoride; ECDI, ethylenecarbodiimide; IB, immunoblot; SI, stimulation index; HEL, hen egg lysozyme; SHAM, BSA-coupled ECDI-fixed splenocytes.