Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivities

Cassandra E. Smith, Stephen D. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

The probability that epitope spreading occurs in multiple sclerosis (MS) and the fact that patients have been shown to respond to multiple myelin epitopes concurrently makes the use of peptide-specific tolerance therapies targeting single epitopes problematic. To attempt to overcome this limitation, we have employed cocktails of peptides in the ECDI coupled-APC tolerance system in mice to determine if T cell responses to multiple autoepitopes can be targeted simultaneously. Preventative tolerance induced with splenocytes coupled with a peptide cocktail of four distinct encephalitogenic epitopes (PLP139-151, PLP178-191, MBP84-104, and MOG92-106) inhibited initiation of active EAE induced with each individual peptide and by a mixture of the four peptides by preventing activation of autoreactive Th1 cells and subsequent infiltration of inflammatory cells into the CNS. Most relevant to treatment of clinical MS, therapeutic tolerance initiated by splenocytes coupled with the peptide cocktail administered at the peak of acute disease prevented clinical relapses due to epitope spreading and ameliorated a diverse disease induced with a mixture of the four peptides. Interestingly, therapeutic tolerance appeared to be mediated by a mechanism distinct from preventative tolerance, i.e. by significantly increasing the levels of production of the anti-inflammatory cytokines TGF-β and/or IL-10 in both the periphery and the CNS.

Original languageEnglish (US)
Pages (from-to)218-231
Number of pages14
JournalJournal of Autoimmunity
Volume27
Issue number4
DOIs
StatePublished - Dec 2006

Keywords

  • Anergy
  • Antigens
  • Autoimmunity
  • EAE/MS
  • Epitopes
  • Peptides
  • Suppression
  • T Cells
  • Tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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