Increased CD74 binding and EAE treatment efficacy of a modified DRα1 molecular construct

Roberto Meza-Romero, Gil Benedek, Grant Gerstner, Gail Kent, Ha Nguyen, Halina Offner, Arthur A. Vandenbark

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system (CNS) with a strong inflammatory component that affects more than 2 million people worldwide (and at least 400,000 in the United States). In MS, macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) enhance the inflammatory event as a result of their interaction with their cognate receptor CD74. Therefore, the search for new agents aimed at blocking this interaction is critical for therapeutic purposes and will be of paramount importance for the treatment of MS. DRα1-MOG-35-55 constructs have been demonstrated to be effective in the treatment of experimental autoimmune encephalomyelitis (EAE) a mouse model for MS. This effect is directly correlated with the binding to its cell surface receptor, CD74, apparently preventing or blocking the binding of two inflammatory factors, MIF and D-DT. Here we report that a single amino acid substitution (L50Q) in the DRα1 domain of the human and mouse DRα1-MOG-35-55 constructs (notated as DRhQ and DRmQ, respectively) possessed increased affinity for CD74, a greater capacity to block MIF binding, the ability to inhibit pERK1/2 signaling and increased therapeutic activity in mice with EAE. These data suggest that binding affinity for CD74 could serve as an in vitro indicator of biological potency of DRhQ and thus support its possible clinical utility as an effective therapy for MS and perhaps other diseases in which there is an inflammatory reaction driven by MIF and D-DT.

Original languageEnglish (US)
Pages (from-to)153-164
Number of pages12
JournalMetabolic brain disease
Volume34
Issue number1
DOIs
StatePublished - Feb 1 2019

Keywords

  • CD74
  • D-dopachrome tautomerase
  • EAE
  • MIF
  • Multiple sclerosis
  • pERK1/2

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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