Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice.
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 approximately 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.
Meagher
Craig
C
Diabetes Center, University of California, San Francisco, CA 94143, USA.
Tang
Qizhi
Q
Fife
Brian T
BT
Bour-Jordan
Helene
H
Wu
Jenny
J
Pardoux
Cecile
C
Bi
Mingying
M
Melli
Kristin
K
Bluestone
Jeffrey A
JA
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010195:Pancreatitis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D000516:alpha-Amylases / Q000276:immunology / Q000378:metabolism
D001324:Autoantigens; D018106:CD28 Antigens; D000516:alpha-Amylases