Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment

Damien Bresson, Georgia Fousteri, Yulia Manenkova, Michael Croft, Matthias von Herrath

Research output: Contribution to journalArticle

Abstract

Antigen-specific therapies are possibly the safest approach to prevent type 1 diabetes (T1D). However their clinical translation has yielded poor results and greater efforts need to be put into the development of novel strategies to ameliorate their clinical outcome. OX40 is a costimulatory molecule expressed by T cells after antigen recognition and has been implicated in the control effector but also regulatory T cells (Tregs) function in vivo. The activity of OX40 signal on Tregs function has been controversial. In this context we investigated whether an anti-OX40 agonist antibody treatment can ameliorate antigen-specific immune intervention for the prevention of T1D. We show that treatment of non-obese diabetic (NOD) mice with an OX40 agonistic antibody (OX86) reduced type 1 diabetes (T1D) incidence by inducing both CD4 +CD25 +Foxp3 + Tregs and CD4 +Foxp3 - T cells expressing the latency-associated peptide (LAP). These OX86-induced CD4 +Foxp3 -LAP + T cells also demonstrated suppressive activity in vitro. A significant increase in protection was observed when OX86 was combined with insulin B9:23 (insB9:23) peptide immunizations. Synergy resulted from an expansion of IL-10-expressing insB9:23-reactive Tregs which augmented the proportion of CD4 + T cells with in vivo suppressive activity. Consequently, CD4 + T cells purified from OX86/insB9:23 combination treatment prevented T1D development when adoptively transferred into recipient mice. These findings suggest that the requirement for OX40 signaling by antigen-induced Tregs can be dominant over its well-documented need for effector memory cell function and may have potentially important implications for improving the clinical translation of antigen-specific prevention of T1D and possibly other autoimmune disorders.

Original languageEnglish
Pages (from-to)342-351
Number of pages10
JournalJournal of Autoimmunity
Volume37
Issue number4
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Immunotherapy
  • Insulin B9-23 peptide
  • OX40
  • Regulatory T cells (Tregs)
  • Tolerance
  • Type 1 diabetes (T1D)

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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