Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells.
Inflammation plays an important role in ischemic stroke and in humans IL-10 may have a beneficial effect in stroke. We mucosally administered myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to C57BL/6 mice before middle cerebral artery occlusion (MCAO) to induce an anti-inflammatory T cell response directed at CNS myelin. Nasal and oral administration of MOG(35-55) peptide decreased ischemic infarct size at 24 and 72 h after MCAO surgery. Nasal MOG(35-55) peptide was most efficacious and reduced infarct size by 70% at 24 h and by 50% at 72 h (p <or= 0.0001 vs control) and also improved behavior score. Immunohistochemistry demonstrated increased IL-10 and reduced IFN-gamma in the area surrounding the ischemic infarct following nasal treatment. Nasal MOG did not reduce infarct size in IL-10-deficient mice. Adoptive transfer of CD4(+) T cells to untreated mice from nasally tolerized mice before MCAO surgery decreased stroke size (p < 0.001 vs control), whereas, CD4(+) T cells from nasally tolerized IL-10-deficient mice had no effect. Our results demonstrate that IL-10-secreting CD4(+) T cells induced by nasal MOG reduce injury following stroke. In addition, we observed a dramatic reduction of CD11b(+) cells in nasal MOG-treated animals. CD11b(+) cells may contribute to secondary infarct expansion by enhancing NO synthesis that may be reduced by elevated IL-10 levels. Modulation of cerebral inflammation by nasal vaccination with myelin Ags that increase IL-10 in the brain may improve outcome after stroke and enhance mechanisms of recovery.
Frenkel
Dan
D
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Huang
Zhihong
Z
Maron
Ruth
R
Koldzic
Djordje N
DN
Hancock
Wayne W
WW
Moskowitz
Michael A
MA
Weiner
Howard L
HL
D000281:Administration, Intranasal; D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage* / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D018928:Immunity, Mucosal / Q000235:genetics; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D014612:Vaccines / Q000008:administration & dosage* / Q000276:immunology
D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D014612:Vaccines; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10