Induction of immunologic tolerance to myelin basic protein prevents central nervous system autoimmunity and improves outcome after stroke.
OBJECTIVE
Animals subjected to an inflammatory insult at the time of stroke are predisposed to the development of an inflammatory autoimmune response to brain. This response is associated with worse neurological outcome. Because induction of immunologic tolerance to brain antigens before stroke onset is associated with improved outcome, we sought to determine whether this paradigm could prevent the deleterious autoimmune response to brain provoked by an inflammatory stimulus at the time of ischemia.


METHODS
Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin by intranasal administration before middle cerebral artery occlusion. At the time of reperfusion, all animals received lipopolysaccharide (1 mg/kg intraperitoneal). Behavioral tests were performed at set time intervals.


RESULTS
One month after middle cerebral artery occlusion, lymphocytes from the spleens of MBP-tolerized animals were less likely to evidence an autoimmune response and more likely to evidence a regulatory response (Treg) toward MBP than those from ovalbumin-tolerized animals. Animals that had an inflammatory response toward MBP (a Th1 response) performed worse on behavioral tests than those that did not. Fractalkine, a surrogate marker of inflammation, was elevated in animals with a Th1 response to MBP.


CONCLUSIONS
These data extend our previous findings and suggest that deleterious autoimmunity to brain antigens can be prevented by prophylactically inducing regulatory T-cell responses to those antigens.
Gee
J Michael
JM
Department of Neurology, University of Washington School of Medicine, Harborview Medical Center, Seattle, WA, USA.
Kalil
Angela
A
Thullbery
Matthew
M
Becker
Kyra J
KJ
D000281:Administration, Intranasal; D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000188:drug therapy* / Q000503:physiopathology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D054428:Chemokine CX3CL1 / Q000032:analysis / Q000097:blood; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D008297:Male; D004676:Myelin Basic Protein / Q000276:immunology* / Q000627:therapeutic use; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D020521:Stroke / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D015415:Biomarkers; D054428:Chemokine CX3CL1; D004676:Myelin Basic Protein; D010047:Ovalbumin