Immunological study of pathogenesis and fibrosis in autoimmune pancreatitis

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Autoimmune pancreatitis (AIP) is a new clinical entity of pancreatic disorder. There are several immunologic and histologic abnormalities specific for the disease, including increased levels of serum IgG4, and infiltration of lymphocytes and IgG4-positive plasmacytes. The role of IgG4 is unclean Recently regulatory T cells (Tregs) have been reported to be involved in the development of various autoimmune diseases and B-cell shifting to IgG4. To clarify the role of Treg in pathophysiology of AIP, we analyzed circulating Tregs in AIP.We recruited 28 patients with MP for this study. For comparison, we also recruited 23 patients with various other pancreatic diseases and 32 healthy subjects as controls. We analyzed Tregs as CD4+CD25high and CD4+CD25+CD45RA+ (naive) from peripheral blood by flow cytometry. In peripheral blood, CD4+CD25high Tregs were significantly increased in AIP patients (2.99±1.75%, p<0.05) compared with alcoholic chronic pancreatitis (CP) (1.65±0.58%, p<0.05), idiopathi … More c CP (1.53±0.56%, p<0.05), and healthy control (1.72±0.81%, p<0.05). Naive Tregs significantly decreased in MP (0.32±0.22%, p<0.005) compared with healthy control (0.83±0.65%). Naive Tregs in AIP tended to be decreased compared with alcoholic CP (0.60±0.45%) and idiopathic CP (0.41±0.31%) (p=0.08). In untreated MP patients, the number of naive Tregs and IgG4 are correlated (R=0.286). Increased number of CD4+CD25high Tregs may influence IgG4 production in AIR while decreased number of naive Tregs may be involved in pathogenesis in AIP.We also established an animal model of autoimmune pancreatitis using Male Wistar Bonn/Kobori rat (WBN/Kob rat), which is a model of spontaneous chronic pancreatitis with widely distributed fibrosis and degeneration of parenchyma with the infiltration of lymphocytes. In addition to pancreatitis, we demonstrated dacryoadenitis in 3 months of age, and sialadenitis, thyroditis, sclerotic cholangitis and even tubulointerstitial nephritis in over 18 months of age of WBN/Kob rats. Infiltration of CD8^+ cells and deposition of tissue-specific IgG2b were observed in the injured pancreas and lacrymal glands. Furthermore, regulatory T cells (Tregs) defined as CD4^+Foxp3^+ cells decreased in the periphery of WBN/Kob rats, which suggests that the onset of these diseases is at least, attributable to the failure in the maintenance of peripheral immune tolerance. These features clearly show that WBN/Kob rats can be a useful animal model for autoimmune pancreatitis with Sjogren-like syndrome or multifocal fibrosclerosis in the human patients. We also show that these autoimmune diseases can be prevented with a newly devised strategy of bone marrow transplantation (BMT) where bone marrow cells (BMCs) are directly injected into the bone marrow cavity; intra BM BMT (IBM-BMT). These results identify the WBN/Kob rat as the first spontaneous animal model of human AIP and multifocal fibrosclerosis.In conclusion, we identified the role of regulatory T cells in the development of autoimmune pancreatitis in human and animal model. Less