? ? Stroke is a leading cause of disability in developed countries. At least 25% of persons who suffer stroke will become infected during the course of their acute stroke, and those who become infected experience more disability than those that remain infection free. How systemic infection contributes to neurological injury during stroke is not well understood. The rationale for the experiments outlined in this proposal is based on the fact that there is a breach in the integrity of the blood-brain barrier (BBB) following stroke that allows the immune system to encounter novel central nervous system (CNS) antigens in both the brain and in peripheral lymphoid organs. The type of immune response generated upon antigen encounter is determined by the composition of the microenvironment at the site of the encounter. The systemic inflammatory response that accompanies an infection could induce the expression of costimulatory molecules and alter the context in which antigens are presented to lymphocytes, thus promoting their sensitization to brain antigens. Preliminary data suggest that animals do develop an autoimmune response to brain following stroke and that lymphocytes sensitized to CNS antigens contribute to cerebral injury, which might explain why infection in the post-stroke period is associated with worse outcome. Manipulating the post-ischemic immune response could therefore be an effective therapeutic intervention for the treatment of stroke. Using an animal model of stroke and a number of in vivo and ex vivo immunologic assays, we plan to confirm and extend our prior findings which show that sensitization to CNS is associated with worse outcome after stroke. The proposed studies will also incorporate sensitive measures of neurological and behavioral performance. More importantly, we hope to show that induction of immunologic tolerance to CNS antigens, even after stroke onset, will prevent the development of CNS autoimmunity; this tolerance should translate to improved outcome from stroke. Given that over 700,000 strokes occur each year in the United States and that at least 175,000 of patients with stroke will develop a concomitant infection, an immune modulating therapy could have significant impact on public health. (End of Abstract) ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056457-02
Application #
7175355
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Jacobs, Tom P
Project Start
2006-02-01
Project End
2010-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$262,384
Indirect Cost
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Becker, Kyra J; Zierath, Dannielle; Kunze, Allison et al. (2016) The contribution of antibiotics, pneumonia and the immune response to stroke outcome. J Neuroimmunol 295-296:68-74
Becker, Kyra J (2016) Strain-Related Differences in the Immune Response: Relevance to Human Stroke. Transl Stroke Res 7:303-12
Zierath, Dannielle; Kunze, Allison; Fecteau, Leia et al. (2015) Promiscuity of autoimmune responses to MBP after stroke. J Neuroimmunol 285:101-5
Zierath, Dannielle; Kunze, Allison; Fecteau, Leia et al. (2015) Effect of Antibiotic Class on Stroke Outcome. Stroke 46:2287-92
Zierath, Dannielle; Schulze, Juliane; Kunze, Allison et al. (2013) The immunologic profile of adoptively transferred lymphocytes influences stroke outcome of recipients. J Neuroimmunol 263:28-34
Becker, Kyra (2012) Autoimmune responses to brain following stroke. Transl Stroke Res 3:310-7
Becker, Kyra J (2012) Activation of immune responses to brain antigens after stroke. J Neurochem 123 Suppl 2:148-55
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
Zierath, Dannielle; Thullbery, Matthew; Hadwin, Jessica et al. (2010) CNS immune responses following experimental stroke. Neurocrit Care 12:274-84
Zierath, Dannielle; Hadwin, Jessica; Savos, Anna et al. (2010) Anamnestic recall of stroke-related deficits: an animal model. Stroke 41:2653-60

Showing the most recent 10 out of 15 publications