Recombinant T Cell Receptor Ligand Treatment Improves Neurological Outcome in the Presence of Tissue Plasminogen Activator in Experimental Ischemic Stroke

Abstract

RTL1000 is a partial human MHC molecule coupled to a human myelin peptide. We previously demonstrated that RTL1000 was protective against experimental ischemic stroke in HLA-DR2 transgenic (DR2-Tg) mice. Since thrombolysis with recombinant tissue plasminogen activator (t-PA) is a standard therapy for stroke, we determined if RTL1000 efficacy is altered when combined with t-PA in experimental stroke. Male DR2-Tg mice underwent 60 min of intraluminal middle cerebral artery occlusion (MCAO). t-PA or vehicle was infused intravenously followed by either a single or 4 daily subcutaneous injections of RTL1000 or vehicle. Infarct size was measured by 2, 3, 5-triphenyltetrazolium chloride staining at 24h or 96 h of reperfusion. Our data showed that t-PA alone reduced infarct size when measured at 24 h but not at 96 h after MCAO. RTL1000 alone reduced infarct size both at 24 and 96h after MCAO. Combining RTL1000 with t-PA did not alter its ability to reduce infarct size at either 24 or 96 h after MCAO and provides additional protection in t-PA treated mice at 24 h after ischemic stroke. Taken together, RTL1000 treatment alone improves outcome and provides additional protection in t-PA treated mice in experimental ischemic stroke.

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

“…A similar effect has also been demonstrated in young female DR2-Tg mice (Pan et al, 2014). We also confirmed that combining RTL1000 with t-PA does not alter its ability to reduce infarct in experimental ischemic stroke (Zhu et al, 2014B). …”

“…The dose and injection protocol of RTL1000 was established in our previous studies (Subramanian et al, 2009; Zhu et al, 2014A; Zhu et al, 2014B). …”

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

“…Male HLA-DRB1*1502 transgenic mice (DR2-Tg, 10–14 weeks of age and weighing 23–28 g) were produced at the Portland VA Medical Center using foundation breeders provided by Dr. Chella David [22]. The mice were housed in temperature-controlled rooms on a 12 hour light and 12-hour dark cycle with water and food ad libitum.…”

“…LDP was measured before CCA ligation (baseline), and measurements continued throughout procedure and 5 min after release of CCA ligature. Animals were excluded if LDP did not drop below 30% of baseline after all thrombin was infused [22]. …”

Translational Stroke Research on Blood-Brain Barrier Damage: Challenges, Perspectives, and Goals

“…First, employment of translatable model systems is essential, e.g. , use of an embolic stroke model that encompasses tPA-induced reperfusion [34, 35]. Future studies are warranted to determine whether early BBB impairment might predict the risk of hemorrhagic transformation upon tPA recanalization and influence stroke prognosis.…”