Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Abstract

BACKGROUND AIMS:: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to development of AIP and new therapeutic strategies. METHODS:: We used quantitative PCR, immunohistochemical and ELISA analyses to measure expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing LT and specifically in acinar cells ( Ela1-LTab mice). RESULTS:: mRNA levels of lymphotoxin (LT) and were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines ( CXCL13, CCL19, CCL21, CCL1 and BAFF) was increased in pancreatic and serum samples from patients. Upregulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LT (Ela1-LT) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LT did not cause autoimmunity in mice without lymphocytes(Ela1-LTab/Rag1(-/-)); moreover lack of pro-inflammatory monocytes (Ela1-LTab/Ccr2-/-) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as anti-pancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS:: Overexpression of LT specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LT R ligands might be used to treat patients with AIP.

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

“…Except for the mice harvested up to 8 h after first ceruleininjection, animals did not receive cerulein or MS-275 on the harvest day. For AIP, we used mice overexpressing LTα and LTβ that develop the disease spontaneously at 12 months of age (Seleznik et al, 2012). Mice were examined throughout the development of pancreatitis and their health status recorded every second day on a score sheet.…”

“…With this aim, we used transgenic mice overexpressing lymphotoxin (LT) α and β in pancreatic acinar cells that spontaneously develop AIP at 12 months of age (Seleznik et al, 2012). Besides developing autoantibodies, these animals are characterized by increased inflammatory infiltration, expression of pro-inflammatory mediators (Supporting Information Figure S3C) and formation of tertiary lymphoid organs in the pancreas (Supporting Information Figure S3D).…”

“…Tgf-β RII (Tgfbr2) fl/fl ] (Grabliauskaite et al, 2016), lymphotoxin (LT) αβ-overexpressing mice (Seleznik et al, 2012) and cyclin-dependent kinase inhibitor (CDK) p21 WAF1/Cip1 knocked-out mice (p21 À/À ) (Jackson Laboratories, USA). Groups of four to five mice were kept in standard individually ventilated cages in a specific pathogen-free facility.…”

“…HDAC expression increased in a time-dependent manner, reaching a plateau after 4 weeks of pancreatitis, with transcripts of class I HDAC being the most abundant (Figure 1 H). Finally, we investigated whether HDAC expression is regulated during the course of autoimmune pancreatitis (AIP).With this aim, we used transgenic mice overexpressing lymphotoxin (LT) α and β in pancreatic acinar cells that spontaneously develop AIP at 12 months of age (Seleznik et al, 2012). Besides developing autoantibodies, these animals are characterized by increased inflammatory infiltration, expression of pro-inflammatory mediators (Supporting Information Figure S3C) and formation of tertiary lymphoid organs in the pancreas (Supporting Information Figure S3D).…”

Republished: Recent advances in autoimmune pancreatitis: type 1 and type 2

“…Further evidence comes from genetically modified animals that were generated to mimic AIP. The most recent example is the lymphotoxin α/β model in which a cytokine from the tumour necrosis factor (TNF) superfamily was first found to be overexpressed in the pancreatic tissue of patients with AIP and then, when overexpressed in the acinar cells of the mouse pancreas, resulted in a disease phenotype that closely mimics AIP 46. The disease severity further depended on the presence of lymphocytes, and steroid treatment could reduce pancreatitis but not the associated production of antibodies.…”