Abstract WP93: CD4+ T Helper Cell Mediated Regulation Of Cerebral Ischemia In Vitamin D Deficient Rats
Stroke is the third leading cause of death worldwide, and Vitamin D deficiency is associated with increased stroke risk, severity, and mortality. Vitamin D potently regulates the immune system and the post-stroke inflammatory response plays a critical role in ischemia-induced CNS pathogenesis; and neuroimmune interactions in the CNS and periphery regulate the nature, extent, and duration of inflammation. Previous studies from this lab indicate that Vitamin D deficiency (VDD) exacerbates ischemic cell loss and sensory motor behavioral deficits in adult rats subject to middle cerebral artery occlusion, an experimental stroke model. Changes in inflammatory cytokines post-ischemia included increased TGF-β expression in both groups but significantly higher IL-6 expression in VDD ischemic cortical tissues than control levels. Increased IL-6 levels in the presence of TGF-β is known to induce pathogenic CD4+ Th17 cell development and suppress neuroprotective Treg generation. In the present studies we used flow cytometry to examine Th17 and Treg subsets in ischemic cortical and splenic tissues. Flow cytometry indicated that VDD rats had significantly less activated Treg cells in ischemic cortical and splenic tissue, while Th17 activation was significantly increased in VDD ischemic cortical tissue. Due to the dysregulation of Treg:Th17 subsets in VDD animals post-stroke and the recently recognized role of the spleen and peripheral nervous system in ischemia-associated neurodegeneration we hypothesized that adoptive transfer of CD4+ T cells harvested from the spleen of control animals 2d post-stroke to the VDD group acutely following middle cerebral artery occlusion (4h) may provide key neuroimmune regulatory elements and/or neuroprotective immune cells and secretions. We found that splenic CD4+ adoptive transfer to VDD rats 4h post-stroke markedly improved infarct volume, survival, and behavioral performance as compared with VDD animals injected with vehicle alone. Together, these results suggest that peripheral immune status significantly influences stroke severity and that acute manipulation of the peripheral immune system post-stroke can prevent or ameliorate inflammation-associated neurodegeneration.
- © 2012 by American Heart Association, Inc.