HLA-DRα1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection

Abstract

BackgroundDRα1-mouse(m)MOG-35-55, a novel construct developed in our laboratory as a simpler and potentially less immunogenic alternative to two-domain class II constructs, was shown previously to target the MIF/CD74 pathway and to reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in DR*1501-Tg mice in a manner similar to the parent DR2β1-containing construct.MethodsIn order to determine whether DRα1-mMOG-35-55 could treat EAE in major histocompatibility complex (MHC)-mismatched mice and to evaluate the treatment effect on central nervous system (CNS) inflammation, C57BL/6 mice were treated with DRα1-mMOG-35-55. In addition, gene expression profile was analyzed in spinal cords of EAE DR*1501-Tg mice that were treated with DRα1-mMOG-35-55.ResultsWe here demonstrate that DRα1-mMOG-35-55 could effectively treat EAE in MHC-mismatched C57BL/6 mice by reducing CNS inflammation, potentially mediated in part through an increased frequency of M2 monocytes in the spinal cord. Microarray analysis of spinal cord tissue from DRα1-mMOG-35-55-treated vs. vehicle control mice with EAE revealed decreased expression of a large number of pro-inflammatory genes including CD74, NLRP3, and IL-1β and increased expression of genes involved in myelin repair (MBP) and neuroregeneration (HUWE1).ConclusionThese findings indicate that the DRα1-mMOG-35-55 construct retains therapeutic, anti-inflammatory, and neuroprotective activities during treatment of EAE across MHC disparate barriers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0342-4) contains supplementary material, which is available to authorized users.

Potential immunotherapies for traumatic brain and spinal cord injury

“…A new bioengineered protein comprised of the human leukocyte antigen (HLA)-DRα1 domain linked covalently to mouse MOG-35-55 peptide (DRα1-MOG-35-55) has been shown to modulate monocyte response 206 , 207 and improve histological and clinical outcomes after TBI. 208 …”

AAV2/9-mediated overexpression of MIF inhibits SOD1 misfolding, delays disease onset, and extends survival in mouse models of ALS

“…Moreover, injection of a MIF antagonist peptide into the spinal cord reduces expression of proinflammatory genes and is neuroprotective in a model of encephalomyelitis (60). These data suggest that MIF elicits its pathological functions in the spinal cord by activation of proinflammatory mechanisms which may induce profound neurotoxic effects in the spinal cord (61).…”

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…However, there were also studies demonstrating the limitation of the application of interferon-β in the treatment of the multiple sclerosis or EAE, showing that interferon-β therapy was effective against multiple sclerosis or EAE only in the NLRP3 inflammasome-dependent EAE ( Inoue et al, 2012 ; Inoue et al, 2016 ). In addition, Benedek et al (2015 , 2017 ) demonstrated that DRα1-mouse(m)MOG-35-55, a less immunogenic alternative to two-domain class II construct developed by their lab, significantly reversed the clinical and histological symptoms of EAE mice through the inhibition of the NLRP3 inflammasome targeting on the MIF/CD74 pathway. Moreover, previous studies in our lab also reported several effective NLRP3 inflammasome inhibitors in the treatment of EAE.…”