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

We have previously demonstrated that recombinant T-cell receptor ligand 1000 (RTL1000) reduces infarct size and improves long-term functional recovery after experimental stroke in young transgenic mice expressing human leukocyte antigen DR2 (DR2-Tg). In this study, we determined the effect of RTL1000 on infarct size in 12-month-old middle-aged DR2-Tg mice, and investigated its mechanism of action. Twelve-month-old male DR2-Tg mice underwent 60min of intraluminal reversible middle cerebral artery occlusion (MCAO). Vehicle or RTL1000 was injected 4, 24, 48 and 72h after MCAO. Cortical, striatal and total hemispheric infarcts were measured 96h after stroke. Spleen and brain tissues were collected 96h after stroke for immunological analysis. Our data showed that RTL1000 significantly reduced infarct size 96h after MCAO in middle-aged male DR2-Tg mice. RTL1000 decreased the number of activated monocytes/microglia cells (CD11b(+)CD45(hi)) and CD3(+) T cells in the ischemic hemisphere. RTL1000 also reduced the percentage of total T cells and inflammatory neutrophils in the spleen. These findings suggest that RTL1000 protects against ischemic stroke in middle-aged male mice by limiting post-ischemic inflammation.

Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis.

The iron chelator, Desferal, suppressed disease activity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and it has been tested in pilot trials for MS. The administration regimen of Desferal is cumbersome and prone to complications. Orally-deliverable, iron chelators have been developed that circumvent these difficulties, and the objective of this study was to test an oral chelator in EAE. SJL mice with active EAE were randomly assigned to receive deferiprone (150 mg/kg) or vehicle (water) 2x/day via gavage. EAE mice given deferiprone had significantly less disease activity and lower levels of inflammatory cell infiltrates (revealed by H&E staining) than EAE mice administered vehicle. T-cell infiltration, assessed by anti-CD3 immunohistochemical staining, also was reduced, although not significantly. Splenocytes cultured from naïve SJL mice were stimulated with anti-CD3 and anti-CD28 with or without 250 microM deferiprone. While approximately 39% of costimulated splenocytes without deferiprone underwent division, only approximately 2.8% of costimulated splenocytes with deferiprone divided and the latter cells were only 53% as viable as the former. Deferiprone had no effect on proliferation or viability of cells that were not costimulated. In summary, deferiprone effectively suppressed active EAE disease and it inhibited T-cell function.