Increased CD74 binding and EAE treatment efficacy of a modified DRα1 molecular construct
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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.
KeywordsMultiple sclerosis CD74 EAE MIF D-dopachrome tautomerase pERK1/2
This work was supported by the National Institute of Allergy and Infectious Diseases award R42AI122574 (AAV), National Institute Of Neurological Disorders And Stroke R01NS080890 and the American Heart Association 17GRNT33220001 (HO), and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Award 2I01 BX000226 (AAV). The contents do not represent the views of the Department of Veterans Affairs or the United States Government. We thank Dr. Yoram Reiter and the Technion Israel for the donation of G4.
This work was funded by the National Institute of Allergy and Infectious Diseases award R42AI122574 (AAV), National Institute Of Neurological Disorders And Stroke R01NS080890 and the American Heart Association 17GRNT33220001 (HO), and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review. Award 2I01 BX000226 (AAV). The contents do not represent the views of the Department of Veterans Affairs or the United States Government.
Compliance with ethical standards
Conflict of interest
Drs. Vandenbark, Offner, Benedek, Meza-Romero and OHSU have a significant financial interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by the OHSU and VA Portland Health Care System Conflict of Interest in Research Committees. The other authors (Grant Gerstner, Gail Kent, Ha Nguyen) declare no conflicts of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.
- Benedek G, Meza-Romero R, Jordan K, Keenlyside L, Offner H, Vandenbark AA (2015) HLA-DRalpha1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection. J Neuroinflammation 12:123. https://doi.org/10.1186/s12974-015-0342-4 CrossRefPubMedPubMedCentralGoogle Scholar
- Herrero-Herranz E, Pardo LA, Gold R, Linker RA (2008) Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol Dis 30:162–173. https://doi.org/10.1016/j.nbd.2008.01.001 CrossRefPubMedGoogle Scholar
- Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747. https://doi.org/10.1146/annurev.immunol.23.021704.115707 CrossRefPubMedGoogle Scholar
- Vandenbark AA et al (2013) A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance. J Autoimmun 40:96–110. https://doi.org/10.1016/j.jaut.2012.08.004 CrossRefPubMedGoogle Scholar
- Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 8:579–621. https://doi.org/10.1146/annurev.iy.08.040190.003051 CrossRefPubMedGoogle Scholar