Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke.

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.

IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells.

CD25(+)CD4(+) regulatory T cells inhibit the activation of autoreactive T cells in vitro and in vivo, and suppress organ-specific autoimmune diseases. The mechanism of CD25(+)CD4(+) T cells in the regulation of experimental autoimmune encephalomyelitis (EAE) is poorly understood. To assess the role of CD25(+)CD4(+) T cells in EAE, SJL mice were immunized with myelin proteolipid protein (PLP)(139-151) to develop EAE and were treated with anti-CD25 mAb. Treatment with anti-CD25 antibody following immunization resulted in a significant enhancement of EAE disease severity and mortality. There was increased inflammation in the central nervous system (CNS) of anti-CD25 mAb-treated mice. Anti-CD25 antibody treatment caused a decrease in the percentage of CD25(+)CD4(+) T cells in blood, peripheral lymph node (LN) and spleen associated with increased production of IFN-gamma and a decrease in IL-10 production by LN cells stimulated with PLP(130-151) in vitro. In addition, transfer of CD25(+)CD4(+) regulatory T cells from naive SJL mice decreased the severity of active EAE. In vitro, anti-CD3-stimulated CD25(+)CD4(+) T cells from naive SJL mice secreted IL-10 and IL-10 soluble receptor (sR) partially reversed the in vitro suppressive activity of CD25(+)CD4(+) T cells. CD25(+)CD4(+) T cells from IL-10-deficient mice were unable to suppress active EAE. These findings demonstrate that CD25(+)CD4(+) T cells suppress pathogenic autoreactive T cells in actively induced EAE and suggest they may play an important natural regulatory function in controlling CNS autoimmune disease through a mechanism that involves IL-10.

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

IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions.

We investigated T cell receptor induced IL-18 secretion, the cellular and molecular mechanisms associated with the induction of IL-18 and the role of IL-18 in IFN-gamma production in the different stages of multiple sclerosis (MS). We found that anti-CD3/CD28 induced IL-18 production by peripheral blood mononuclear cells was increased in both relapsing-remitting and secondary progressive MS. In controls and relapsing-remitting MS neutralizing anti-IL-12 and anti-IL-18 alone equally suppressed IFN-gamma production whereas in progressive MS, maximum suppression of IFN-gamma was only observed when neutralizing anti-IL-12 and anti-IL-18 were given together, suggesting that in progressive MS, IL-12 and IL-18 function in a non-linked manner to induce IFN-gamma. Elevated IL-18 production in MS was dependent on the interaction of antigen presenting cells with activated CD4(+) T cells via CD40-CD40 ligand and the levels of IL-18 correlated with disease duration in secondary progressive MS. These results demonstrated that IL-18 has an important role in augmenting Th-1 type immune responses in MS and may be involved in immune changes that occur when patients enter the progressive stage.