This proposal is a competing renewal which aims to better understand why infection, which is common after stroke, negatively impacts outcome. Our research demonstrates that an immune response to central nervous system (CNS) antigens occurs after stroke and that the nature of this immune response depends upon the experimental conditions and affects neurological outcome. Specifically, Lewis rats that develop a TH1 type immune response to brain antigens experience worse outcome while Lewis rats that develop a regulatory type response (TREG) experience better outcome. The predisposition to developing a TH1 response is increased by systemic inflammation induced with lipopolysaccharide (LPS). We believe that this model may help to explain why patients who develop an infection following stroke experience worse outcome. The goals of the current project are to assess the "clinical relevance" of our model by validating our findings using a true infection model. We further aim to better define the nature and regulation of this post-ischemic immune response and assess the effect of antibiotic therapy and the role of the sympathetic nervous system on this response. The primary hypothesis to be addressed in the research outlined is: does systemic infection in the immediate post-stroke period increase the likelihood of developing a detrimental autoimmune response to CNS antigens?

Public Health Relevance

Infection is common after stroke and is associated with worse outcome. It is possible that this detrimental effect is mediated by the development of an autoimmune response to brain, and as such, could be modulate to improve outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056457-08
Application #
8512809
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bosetti, Francesca
Project Start
2006-02-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$326,140
Indirect Cost
$115,046
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Savos, Anna V; Gee, J Michael; Zierath, Dannielle et al. (2011) ýý-MSH: a potential neuroprotective and immunomodulatory agent for the treatment of stroke. J Cereb Blood Flow Metab 31:606-13
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Zierath, Dannielle; Thullbery, Matthew; Hadwin, Jessica et al. (2010) CNS immune responses following experimental stroke. Neurocrit Care 12:274-84
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Gee, J Michael; Kalil, Angela; Shea, Connor et al. (2007) Lymphocytes: potential mediators of postischemic injury and neuroprotection. Stroke 38:783-8