DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury

Yang, Liu; Liu, Zhijia; Ren, Honglei; Zhang, Lei; Gao, Siman; Ren, Li; Chai, Zhi; Meza-Romero, Roberto; Benedek, Gil; Vandenbark, Arthur A.; Offner, Halina; Li, Minshu

doi:10.1007/s11011-017-9991-6

Cited by 15 publications

(13 citation statements)

References 23 publications

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“…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 …”

Section: Immunotherapy At the Innate Immune Response After Cns Injurymentioning

confidence: 99%

Potential immunotherapies for traumatic brain and spinal cord injury

Putatunda

Bethea

2018

Chinese Journal of Traumatology

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Traumatic injury of the central nervous system (CNS) including brain and spinal cord remains a leading cause of morbidity and disability in the world. Delineating the mechanisms underlying the secondary and persistent injury versus the primary and transient injury has been drawing extensive attention for study during the past few decades. The sterile neuroinflammation during the secondary phase of injury has been frequently identified substrate underlying CNS injury, but as of now, no conclusive studies have determined whether this is a beneficial or detrimental role in the context of repair. Recent pioneering studies have demonstrated the key roles for the innate and adaptive immune responses in regulating sterile neuroinflammation and CNS repair. Some promising immunotherapeutic strategies have been recently developed for the treatment of CNS injury. This review updates the recent progress on elucidating the roles of the innate and adaptive immune responses in the context of CNS injury, the development and characterization of potential immunotherapeutics, as well as outstanding questions in this field.

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Section: Immunotherapy At the Innate Immune Response After Cns Injurymentioning

confidence: 99%

Potential immunotherapies for traumatic brain and spinal cord injury

Putatunda

Bethea

2018

Chinese Journal of Traumatology

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“…TBI-related nerve injury is attributed to both primary and secondary injury mechanisms (4,5). Primary injury manifests as immediate damage, whilst secondary injury is a long-term process, accompanied by oxidative stress, neuronal apoptosis and an inflammatory response (2,6–8), ultimately leading to neuronal death. There is growing evidence that inflammation and oxidative stress serve pivotal roles in the course of secondary brain injury (10–12).…”

Section: Introductionmentioning

confidence: 99%

Edaravone attenuates traumatic brain injury through anti‑inflammatory and anti‑oxidative modulation

Zhang

Teng

et al. 2019

Exp Ther Med

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Traumatic brain injury (TBI) is among the leading causes of irreversible neurological damage and death worldwide. The aim of the present study was to investigate whether edaravone (EDA) had a neuroprotective effect on TBI as well as to identify the potential mechanism. Results demonstrated that EDA suppressed inflammatory and oxidative responses in mice following TBI. This was evidenced by a reduction in glutathione peroxidase, interleukin 6, tumor necrosis factor-α and hydrogen peroxide levels, in addition to an increase in hemeoxygenase-1, quinone oxidoreductase 1 and superoxide dismutase levels, thereby mitigating neurofunctional deficits, cell apoptosis and structural damage. EDA prevented the transfer of NF-κB protein from the cytoplasm to the nucleus, whilst promoting the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein in mice following TBI. These results indicated that EDA exerted neuroprotective effects, including impeding neurofunctional deficits, cell apoptosis and structural damage, in mice with TBI, potentially via suppression of NF-κB-mediated inflammatory activation and promotion of the Nrf2 antioxidant pathway.

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“…As shown above, we have demonstrated the ability of the DRα1-mMOG-35-55 construct to reduce CNS inflammation and tissue injury in animal models of multiple sclerosis, ischemic injury, and methamphetamine addiction. Thus, we sought to determine if DRα1-mMOG-35-55 treatment of a fluid percussion injury (FPI) mouse model of TBI could reduce the lesion size and improve disease outcome measures [87].…”

Section: Introductionmentioning

confidence: 99%

“…This study provides the first evidence that DRα1-MOG-35-55 treatment improves the outcome of TBI. Our results demonstrate that daily s.c. administration of DRα1-MOG-35-55 can significantly enhance functional outcomes, reduce brain lesion size, block infiltration of CD11b + cells into the injured brain, and promote an anti-inflammatory phenotype in activated CD11b + CD45 hi cells that infiltrate from the periphery or that result from local activation of resident CD11b + CD45 int microglia after TBI [87]. These anti-inflammatory changes observed in the injured brain were in stark contrast with increased numbers of activated monocytes in the blood that were inhibited from crossing the blood-brain barrier into the CNS and the lack of any demonstrable changes in the spleen (not shown).…”

Section: Introductionmentioning

confidence: 99%

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

Vandenbark

Meza-Romero

Benedek

et al. 2019

J Neuroinflammation

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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.

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DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury

Cited by 15 publications

References 23 publications

Potential immunotherapies for traumatic brain and spinal cord injury

Potential immunotherapies for traumatic brain and spinal cord injury

Edaravone attenuates traumatic brain injury through anti‑inflammatory and anti‑oxidative modulation

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

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