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

Abstract

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.

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

“…Additionally, treatment of thromboembolic mice with RTL1000 significantly reduced total infarct volume similar to its treatment of MCAO, thus providing additional proof-of-principal therapeutic benefit in a model that better mimics human stroke pathogenesis (Dotson et al, 2016). …”

Sex differences in the immune response to experimental stroke: Implications for translational research

“…Recombinant T-cell receptor ligand (RTL) has been uysed to treat experimental stroke in mice (Burrows et al, 1998(Burrows et al, , 2001Vandenbark et al, 2003;Huan et al, 2004;Subramanian et al, 2009;Akiyoshi et al, 2011;Dotson et al, 2014Dotson et al, , 2016a. RTL molecules consist of the a1 and b1 domains of MHC class II molecules expressed as a single polypeptide with or without antigenic amino terminal extensions (Burrows et al, 1999;Vandenbark et al, 2003).…”

The Role of Inflammatory Response in Stroke Associated Programmed Cell Death

“…this article, we will outline main pathophysiological processes associated with stroke with an accent to the inflammation and cell death after stroke. Stroke research is a very dynamic process, new information about pathophysiology of stroke allow researchers to view the problematic from new perspectives and to create new models for research which in turn may bring new information [5, 6].…”