Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and experimental autoimmune encephalomyelitis severity in the absence of IL-12 receptor signaling

Denise C. Fitzgerald, Guang Xian Zhang, Shuo Yu, Melissa L. Cullimore, Zhao Zhao, Abdolmohamad Rostami

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rβ2-/- mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rβ2-/- mice however the effect was somewhat less potent in the absence of IL-12Rβ2. Expression of pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-2, was inhibited in wild-type tolerized mice but less so in IL-12Rβ2-/- mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS.

Original languageEnglish (US)
Pages (from-to)32-37
Number of pages6
JournalJournal of Neuroimmunology
Volume247
Issue number1-2
DOIs
StatePublished - Jun 15 2012

Keywords

  • Autoimmunity
  • Experimental autoimmune encephalomyelitis
  • IL-12 receptor
  • Tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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