Recombinant T cell receptor ligand treats experimental stroke.
OBJECTIVE
Experimental stroke induces a biphasic effect on the immune response that involves early activation of peripheral leukocytes followed by severe immunodepression and atrophy of the spleen and thymus. In tandem, the developing infarct is exacerbated by influx of numerous inflammatory cell types, including T and B lymphocytes. These features of stroke prompted our use of recombinant T cell receptor ligands (RTL), partial major histocompatibility complex Class II molecules covalently bound to myelin peptides. We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function.


METHODS
Four daily doses of RTL were administered subcutaneously to C57BL/6 mice after middle cerebral artery occlusion, and lesion size and cellular composition were assessed in the brain and cell numbers were assessed in the spleen and thymus.


RESULTS
Treatment with RTL551 (I-A(b) molecule linked to MOG-35-55 peptide) reduced cortical and total stroke lesion size by approximately 50%, inhibited the accumulation of inflammatory cells, particularly macrophages/activated microglial cells and dendritic cells, and mitigated splenic atrophy. Treatment with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide) similarly reduced the stroke lesion size in HLA-DR2 transgenic mice. In contrast, control RTL with a nonneuroantigen peptide or a mismatched major histocompatibility complex Class II moiety had no effect on stroke lesion size.


CONCLUSIONS
These data are the first to demonstrate successful treatment of experimental stroke using a neuroantigen-specific immunomodulatory agent administered after ischemia, suggesting therapeutic potential in human stroke.
Subramanian
Sandhya
S
Neuroimmunology Research, Portland VA Medical Center, Portland, OR 97239, USA.
Zhang
Bing
B
Kosaka
Yasuharu
Y
Burrows
Gregory G
GG
Grafe
Marjorie R
MR
Vandenbark
Arthur A
AA
Hurn
Patricia D
PD
Offner
Halina
H
D000818:Animals; D001284:Atrophy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007155:Immunologic Factors / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology*; D007279:Injections, Subcutaneous; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000473:pathology; D013154:Spleen / Q000473:pathology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology*; D013950:Thymus Gland / Q000473:pathology
D007155:Immunologic Factors; D008024:Ligands; C542328:RTL1000 protein; C542327:RTL551 protein; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins