myelin-oligodendrocyte-glycoprotein-(35-55) and Stroke

Topics: Animals; Chloride-Bicarbonate Antiporters; Disease Models, Animal; Infarction, Middle Cerebral Artery; Macrophages; Mice, Inbred C57BL; Microglia; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Stroke; Sulfate Transporters

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.

Topics: Animals; Brain; Brain Ischemia; Disease Models, Animal; Female; HLA-DR Antigens; Humans; Ligands; Mice; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Peptide Fragments; Receptors, Antigen, T-Cell; Recombinant Fusion Proteins; Recovery of Function; Sex Factors; Stroke; Vocalization, Animal

Mucosal tolerance has been used successfully to treat animal models of autoimmune diseases and is being tested in human diseases. In this work we demonstrate the reduction of infarct size following mucosal tolerance by myelin oligodendrocyte glycoprotein (MOG) (35-55) peptide in mouse stroke model. Nasal MOG was most efficacious and reduced ischemic infarct size by 70% at 24 h as well as improving behavior score. Using immunohistological methods and IL-10 -/- mice, we demonstrate the importance of IL-10-producing CD4+ T cells in the reduction of the ischemic infarct volume following middle cerebral artery occlusion (MCAO). Furthermore, adoptive transfer of CD4+ T cells from nasally tolerized mice to untreated mice prior to MCAO surgery significantly decreased stroke size (p<0.001 vs. control), whereas CD4+ T cells from nasally tolerized IL-10-deficient mice had no significant effect. Based on these results, modulation of cerebral inflammation by mucosal tolerance to myelin antigens may have applicability both as prophylactic therapy and treatment following ischemia attacks.

Topics: Analysis of Variance; Animals; Antigens, CD; Behavior, Animal; Brain Infarction; CD4-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Immune Tolerance; Immunohistochemistry; Infarction, Middle Cerebral Artery; Interleukin-10; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Immunological; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Severity of Illness Index; Stroke; Time Factors