Amelioration of Murine Autoimmune Pancreatitis by Targeted LTβR Inhibition and Anti-CD20 Treatment

Immunohorizons. 2020 Nov 5;4(11):688-700. doi: 10.4049/immunohorizons.2000079.


Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, for which treatment options, especially the long-term management, are limited. The only therapy that has been established and accepted so far is corticosteroids, but the relapse rate is significant. In the current study, we discern the effector mechanisms of targeted LTβR pathway inhibition using LTβR-Ig. Furthermore, the efficacy of LTβR-Ig therapy is compared with the depletion of immune cell subsets (CD4+ and CD20+), which are suggested to play a pathological role in AIP development. Three well-established mouse models of AIP were used to examine treatment efficacies and mechanisms. Tg(Ela1-Lta,b) mice represent a genetic model, in which AIP develops spontaneously. In MRL/Mp and IL-10-/- mice, AIP is induced by repeated polyinosinic:polycytidylic acid injection. Mice with AIP were treated with anti-CD20, anti-CD4 mAbs, or targeted LTβR-Ig. LTβR-Ig and anti-CD20 treatment led to significant improvement of AIP, including a decrease in autoantibody production and pancreatic inflammation in Tg(Ela1-Lta,b) and IL-10-/- mice. The molecular mechanism of this beneficial effect possibly involves the downregulation of Stat3 and noncanonical NF-κb activation. Anti-CD4 treatment reduced Th1 and Th2 signature but did not alleviate AIP. Additionally, in contrast to anti-CD20 or anti-CD4 treatments, blocking LTβR signaling disrupted tertiary lymphoid organs in all three models. We demonstrate that treatment with LTβR-Ig or anti-CD20 Ab alleviated murine AIP. LTβR-Ig treatment for AIP was effective in both lymphotoxin-dependent and lymphotoxin-independent AIP models, possibly because of its dual anti-inflammatory and antiautoimmune mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, CD20 / immunology
  • Autoimmune Pancreatitis / chemically induced
  • Autoimmune Pancreatitis / drug therapy*
  • Autoimmune Pancreatitis / pathology
  • CD4 Antigens / immunology
  • Disease Models, Animal
  • Female
  • Immunoglobulin G / pharmacology*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Lymphotoxin beta Receptor / drug effects*
  • Lymphotoxin beta Receptor / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Poly I-C / administration & dosage
  • Signal Transduction / immunology


  • Antibodies, Monoclonal
  • Antigens, CD20
  • CD4 Antigens
  • IL10 protein, mouse
  • Immunoglobulin G
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • Interleukin-10
  • Poly I-C