Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment

Schwaiger, Theresa; Brandt, Cindy van den; Fitzner, Brit; Zaatreh, Sarah; Kraatz, Franziska; Dummer, A.; Nizze, H; Evert, Matthias; Bröker, Barbara M.; Brunner‐Weinzierl, Monika C.; Wartmann, Thomas; Salem, Tareq; Lerch, Markus M.; Jaster, Robert; Mayerle, Julia

doi:10.1136/gutjnl-2012-303635

Cited by 61 publications

(79 citation statements)

References 64 publications

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“…Consistent with previous reports (27,31), MRL/Mp mice treated with poly (I:C) exhibited several important histological features of pancreatitis that were similar to human AIP. Thus, after treatment with poly (I:C), the pancreatic tissue of MRL/Mp mice exhibited a massive infiltration of immune cells, destruction of the pancreatic acinar architecture, and pancreatic fibrosis (Fig.…”

Section: Resultssupporting

confidence: 79%

“…In our initial studies, we used a well-established animal model of human AIP to identify the type of immune cells and cytokines that might be involved in the development of human AIP (27,31). Consistent with previous reports (27,31), MRL/Mp mice treated with poly (I:C) exhibited several important histological features of pancreatitis that were similar to human AIP.…”

Section: Resultssupporting

confidence: 61%

“…Histopathological evaluation of pancreatic lesions was performed to assess the degree of inflammatory cell infiltration (22,23,27). Inflammatory infiltrates were scored as follows: 0, pancreas without mononuclear cell infiltration; 1, mononuclear cell aggregation and/or infiltration within the interstitium, with no parenchymal destruction; 2, focal parenchymal destruction with mononuclear cell infiltration; 3, diffuse parenchymal destruction but some intact parenchymal residue retained; and 4, almost all pancreatic tissue, except the pancreatic islets, destroyed or replaced with fibrosis or adipose tissue (22).…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

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Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Arai

Yamashita

Kuriyama

et al. 2015

The Journal of Immunology

132

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The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-α production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-α, and with pDC depletion and IFN-α-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-α. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-α–expressing pDCs and had significantly higher serum IFN-α levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-α and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-α is a major cause of murine AIP; in addition, the increased pDC production of IFN-α and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.

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Section: Resultssupporting

confidence: 79%

Section: Resultssupporting

confidence: 61%

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

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Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Arai

Yamashita

Kuriyama

et al. 2015

The Journal of Immunology

132

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“…Recently, Schwaiger et al published a study using a murine model showing that an alternative immunomodulatory agent may be more effi cacious than azathioprine [ 9 ]. They developed a model in MRL/Mp female mice that when exposed to polyinosinic:polycytidylic acid induces an infl ammatory condition that mimics the histologic and phenotypic features of human type 1 AIP.…”

Section: Future Studiesmentioning

confidence: 97%

Treatment: Immunomodulatory Drugs and Rituximab

Hart

Chari

2014

Autoimmune Pancreatitis

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“…Therefore, interventions targeting the armory of disease-causing inflammatory cells and molecules have been proposed and tested. As listed in Table 1, non-specific interventions that are routinely used include depletion of cell populations by cyclophosphamide, 18 depletion of cell subset by antibodies(anti-CD3 mAb for T cell depletion 29 or anti-CD20 mAb for B cell depletion 30,31 ]), depletion of inflammatory cytokines by antibody, 32,33 universal tolerance induction by immunosuppressant drugs (dexamethasone, FK506, rapamycin or cyclosporin A), [34][35][36] entrapment of all leukocyte into lymph nodes away from inflammatory tissues (FTY720), 37,38 etc. As already pointed out above, these approaches run into the risk of increasing the chance of infection and tumorigenesis (Fig.…”

Section: Taming Inflammationmentioning

confidence: 99%