A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury

Arthur A. Vandenbark, Roberto Meza-Romero, Gil Benedek, Halina Offner

Research output: Contribution to journalReview article

4 Scopus citations

Abstract

Neurovascular, autoimmune, and traumatic injuries of the central nervous system (CNS) all have in common an initial acute inflammatory response mediated by influx across the blood-brain barrier of activated mononuclear cells followed by chronic and often progressive disability. Although some anti-inflammatory therapies can reduce cellular infiltration into the initial lesions, there are essentially no effective treatments for the progressive phase. We here review the successful treatment of animal models for four separate neuroinflammatory and neurodegenerative CNS conditions using a single partial MHC class II construct called DRa1-hMOG-35-55 or its newest iteration, DRa1(L50Q)-hMOG-35-55 (DRhQ) that can be administered without a need for class II tissue type matching due to the conserved DRα1 moiety of the drug. These constructs antagonize the cognate TCR and bind with high affinity to their cell-bound CD74 receptor on macrophages and dendritic cells, thereby competitively inhibiting downstream signaling and pro-inflammatory effects of macrophage migration inhibitory factor (MIF) and its homolog, d-dopachrome tautomerase (D-DT=MIF-2) that bind to identical residues of CD74 leading to progressive disease. These effects suggest the existence of a common pathogenic mechanism involving a chemokine-driven influx of activated monocytes into the CNS tissue that can be reversed by parenteral injection of the DRa1-MOG-35-55 constructs that also induce anti-inflammatory macrophages and microglia within the CNS. Due to their ability to block this common pathway, these novel drugs appear to be prime candidates for therapy of a wide range of neuroinflammatory and neurodegenerative CNS conditions.

Original languageEnglish (US)
Article number14
JournalJournal of Neuroinflammation
Volume16
Issue number1
DOIs
StatePublished - Jan 23 2019

Keywords

  • DRhQ
  • Inflammation
  • Ischemic injury
  • Macrophage migration inhibitory factor
  • Methamphetamine addiction
  • Multiple sclerosis
  • Neurotherapy
  • Partial MHC class II constructs
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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