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.
Diabetes Center, University of California, San Francisco, CA 94143, USA.
Craig
C
Meagher
Qizhi
Q
Tang
Brian T
BT
Fife
Helene
H
Bour-Jordan
Jenny
J
Wu
Cecile
C
Pardoux
Mingying
M
Bi
Kristin
K
Melli
Jeffrey A
JA
Bluestone
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