Recombinant T-cell receptor ligand RTL1000 limits inflammation and decreases infarct size after experimental ischemic stroke in middle-aged mice

Zhu, Wenbin; Dotson, Abby L.; Libal, Nicole L.; Lapato, Andrew; Bodhankar, Sheetal; Offner, Halina; Alkayed, Nabil J.

doi:10.1016/j.neuroscience.2014.12.037

Cited by 18 publications

(13 citation statements)

References 32 publications

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“…We hypothesize that in old mice RTL1000 treatment might induce the migration of regulatory CD8 + cells (CD8 + CD122 + IL-10 + ) into the CNS, whereas in RTL1000-treated young mice these cells are retained in the periphery. Our studies suggest that age-dependent differences in the immune response after ischemic stroke results in pMHC protection from experimental stoke through peripheral-based immune regulation in young mice and inflammatory tissue-specific protection in older mice (Dotson et al, 2014; Zhu et al, 2015b). These studies address the interaction of stroke therapy with age, one of the important factors that contribute to the likelihood of a success in clinical trials.…”

Section: Treating Stroke In Middle-aged and Old Mice With Partial Mhcmentioning

confidence: 74%

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

Benedek

Vandenbark

Alkayed

et al. 2017

Neurochemistry International

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The worldwide prevalence of stroke continues to rise despite recent successes in treating acute ischemic stroke. With limited patient eligibility and associated risk of tPA and mechanical thrombectomy, new preventive and therapeutic modalities are needed to stave the rising wave of stroke. Inflammation plays a key role in brain damage after cerebral ischemia, and novel therapies that target pro-inflammatory cells have demonstrated promise for treatment for stroke. Partial MHC class II constructs have been shown to prevent and/or reverse clinical signs of various inflammatory diseases such as experimental autoimmune encephalomyelitis, collagen-induced arthritis and experimental autoimmune uveitis, by reducing the number and frequency of activated cells in the damaged CNS. Herein, we review the use of partial MHC class II constructs as a novel treatment for ischemic stroke. These constructs have been shown to reduce infarct volume and neurological deficit in various cerebral ischemia models in young adult and aging male and female mice. In addition, partial MHC class II constructs were shown to reverse stroke-associated splenic atrophy and promote a protective M2 macrophage/microglia phenotype in the CNS which contributes to tissue repair and recovery after stroke. By addressing remaining STAIR criteria, such as efficacy in large animal models of stroke, these constructs will be prime candidates for clinical trials of acute ischemic stroke.

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Section: Treating Stroke In Middle-aged and Old Mice With Partial Mhcmentioning

confidence: 74%

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

Benedek

Vandenbark

Alkayed

et al. 2017

Neurochemistry International

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“…Our lab has previously shown that RTLs could treat both experimental autoimmune encephalomyelitis (EAE) and experimental stroke induced by transient MCAO in mice [23, 39, 37, 40, 41, 21, 42, 43]. RTL1000 is comprised of an HLA-DR2 α1β1 moiety linked to human MOG-35-55 peptide [44] and has been shown to reduce infarct size in young, middle aged and older humanized DR2 mice treated with RTL following experimental stroke [21, 45, 22, 27, 46]. RTL1000, delivered one hour after stroke onset significantly reduced neurological scores and infarct volumes in the cortex and hemisphere after 24 hours.…”

Section: Discussionmentioning

confidence: 99%

Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion

Dotson

Chen

Zhu

et al. 2015

Transl. Stroke Res.

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Inflammation and thrombosis are tightly linked, with inflammation contributing to thromboembolism and to stroke outcome. Thromboembolism is a frequent cause of ischemic stroke, yet the most used occlusion mouse models of experimental stroke do not effectively replicate thromboembolism. Our group recently described a novel thromboembolic mouse model of stroke that successfully occludes the middle cerebral artery with high reproducibility. In the current study, we characterize the peripheral and local immune outcomes as well as the ischemic response to immune therapy in a clinically relevant mouse model of thromboembolic stroke. Brain and spleen tissues were harvested 24 hours after thromboembolic stroke and cells immunophenotyped by flow cytometry. We observed a significant increase in neutrophils and early activated T cells in the spleen and an increase in neutrophils and activated monocytes/microglia in the ischemic cortex after thromboembolic stroke. Moreover, as was shown previously for transient MCAO models, treatment of thromboembolic stroke with partial MHC constructs significantly reduced ischemic damage indicating an equivalent effect of this immune-based therapy in the thromboembolic model that better mimics the pathophysiology of human stroke.

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“…administered very late antigen‐4 and its counterpart vascular cell adhesion molecule‐1 via monoclonal antibodies, which improved the outcome of stroke lesions by inhibiting lymphocyte invasion . Moreover, recombinant T‐cell receptor ligands and lymphocyte egress inhibitors such as fingolimoid have also been successful in murine models of stroke …”

Section: Lymphocytes Encompass Adaptive Immune‐mediated Responses Folmentioning

confidence: 99%

“…96 Moreover, recombinant T-cell receptor ligands and lymphocyte egress inhibitors such as fingolimoid have also been successful in murine models of stroke. [97][98][99] Given the heterogeneity of T-cell phenotype, over the past 10 years researchers have been trying to elucidate the T-cell-specific factors responsible for contributing to stroke pathology. Shichita et al showed that cd T cells, but not conventional CD4 + T cells, can produce IL-17 following tMCAO, which contributes to ischaemic brain injury in an IL-23-dependent manner.…”

Section: Lymphocytes Encompass Adaptive Immunemediated Responses Follmentioning

confidence: 99%

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

et al. 2018

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Stroke is one of the leading causes of death and disability worldwide. The long-standing dogma that stroke is exclusively a vascular disease has been questioned by extensive clinical findings of immune factors that are associated mostly with inflammation after stroke. These have been confirmed in preclinical studies using experimental animal models. It is now accepted that inflammation and immune mediators are critical in acute and long-term neuronal tissue damage and healing following thrombotic and ischaemic stroke. Despite mounting information delineating the role of the immune system in stroke, the mechanisms of how inflammatory cells and their mediators are involved in stroke-induced neuroinflammation are still not fully understood. Currently, there is no available treatment for targeting the acute immune response that develops in the brain during cerebral ischaemia. No new treatment has been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. Here, we review current knowledge of the immunity of stroke and identify critical gaps that hinder current therapies. We will discuss advances in the understanding of the complex innate and adaptive immune responses in stroke; mechanisms of immune cell-mediated and factor-mediated vascular and tissue injury; immunity-induced tissue repair; and the importance of modulating immunity in stroke.

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Recombinant T-cell receptor ligand RTL1000 limits inflammation and decreases infarct size after experimental ischemic stroke in middle-aged mice

Cited by 18 publications

References 32 publications

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

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