Novel humanized recombinant T cell receptor ligands protect the female brain after experimental stroke.
Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice with middle cerebral artery occlusion (MCAO). HLA-DR2 transgenic female mice with MCAO were treated with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide), HLA-DRa1-MOG-35-55, or vehicle (VEH) at 3, 24, 48, and 72 h after reperfusion and were recovered for 96 h or 2 weeks post-injury for measurement of histology (TTC staining) or behavioral testing. RTL1000- and DRa1-MOG-treated mice had profoundly reduced infarct volumes as compared to the VEH group, although higher doses of DRa1-MOG were needed for females vs. males evaluated previously. RTL1000-treated females also exhibited strongly improved functional recovery in a standard cylinder test. In novel studies of post-ischemic ultrasonic vocalization (USV), as measured by animal calls to their cage mates, we modeled in mice the post-stroke speech deficits common in human stroke survivors. The number of calls was reduced in injured animals relative to pre-MCAO baseline regardless of RTL1000 treatment status. However, call duration was significantly improved by RTL1000 treatment, suggesting benefit to the animal's recovery of vocalization capability. We conclude that both the parent RTL1000 molecule and the novel non-polymorphic DRα1-MOG-35-55 construct were highly effective immunotherapies for treatment of transient cerebral ischemia in females.
Nanjing University Medical School, Nanjing, People's Republic of China.
Jie
J
Pan
Julie
J
Palmateer
Timothy
T
Schallert
Madison
M
Hart
Arushi
A
Pandya
Arthur A
AA
Vandenbark
Halina
H
Offner
Patricia D
PD
Hurn
D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006684:HLA-DR Antigens / Q000627:therapeutic use*; D006801:Humans; D008024:Ligands; D051379:Mice; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D020127:Recovery of Function; D012737:Sex Factors; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D014828:Vocalization, Animal
D006684:HLA-DR Antigens; D008024:Ligands; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C542328:RTL1000 protein; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55)