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

J Autoimmun. 2011 Dec;37(4):342-51. doi: 10.1016/j.jaut.2011.10.001. Epub 2011 Nov 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • CD4 Antigens / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / prevention & control
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immunosuppression
  • Insulin / administration & dosage
  • Interleukin-10 / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred NOD
  • Peptide Fragments / administration & dosage
  • Receptors, OX40 / agonists*
  • Receptors, OX40 / immunology
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Antibodies, Monoclonal
  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Insulin
  • Interleukin-2 Receptor alpha Subunit
  • Peptide Fragments
  • Receptors, OX40
  • Transforming Growth Factor beta1
  • insulin B (9-23)
  • Interleukin-10